Small-Molecule Kinase Inhibitors for the Treatment of Nononcologic Diseases
- Zhouling XieZhouling XieDepartment of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, ChinaMore by Zhouling Xie,
- Xiaoxiao YangXiaoxiao YangDepartment of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, ChinaMore by Xiaoxiao Yang,
- Yajun DuanYajun DuanDepartment of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, ChinaMore by Yajun Duan,
- Jihong HanJihong HanDepartment of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, ChinaMore by Jihong Han, and
- Chenzhong Liao*Chenzhong Liao*E-mail: [email protected], [email protected]Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, ChinaMore by Chenzhong Liao
Copyright © 2021 American Chemical Society
Abstract
Great successes have been achieved in developing small-molecule kinase inhibitors as anticancer therapeutic agents. However, kinase deregulation plays essential roles not only in cancer but also in almost all major disease areas. Accumulating evidence has revealed that kinases are promising drug targets for different diseases, including cancer, autoimmune diseases, inflammatory diseases, cardiovascular diseases, central nervous system disorders, viral infections, and malaria. Indeed, the first small-molecule kinase inhibitor for treatment of a nononcologic disease was approved in 2011 by the U.S. FDA. To date, 10 such inhibitors have been approved, and more are in clinical trials for applications other than cancer. This Perspective discusses a number of kinases and their small-molecule inhibitors for the treatment of diseases in nononcologic therapeutic fields. The opportunities and challenges in developing such inhibitors are also highlighted.
1. Introduction
ARTICLE SECTIONS
As a large and varied multigene family of enzymes, kinases catalyze the transfer of the γ-phosphate group from the high-energy ATP molecule to specific substrates. Referred to as phosphorylation, this process produces a phosphorylated product and ADP. On the basis of the substrates they phosphorylate, kinases are classified into protein kinases, lipid kinases, carbohydrate kinases, and other kinases. Generally, phosphate groups are added to serine, threonine, or tyrosine residues in proteins. The phosphorylation state of a molecule has a large impact on its activity, reactivity, and capacity to bind other molecules. Kinases are pivotal in cell signaling, metabolism, protein regulation, secretory processes, cellular transport, and many other cellular pathways, therefore, kinases are crucial in human physiology. To date, 518 different kinases have been identified in humans, and they phosphorylate up to one-third of the proteome.(1) Deregulation of kinase signaling has been confirmed to play indispensable roles in virtually all major disease areas, including oncological, immunological, inflammatory, degenerative, metabolic, cardiovascular, and infectious diseases, therefore, kinases have been intensively investigated for drug development in different disease fields.(2−4)
Kinase inhibitors can be classified according to their structure and size as monoclonal antibodies (mAbs) or small-molecule kinase inhibitors (SMKIs). Spectacular successes have been achieved in developing mAbs as anticancer therapeutic agents. For example, as early as 1998, the first mAb, trastuzumab, was approved by the U.S. Food and Drug Administration (FDA) for treatment of HER2 receptor-positive breast cancer. However, because of the inherent disadvantages of mAbs, such as production cost, stability, and immunogenicity,(5) low-molecular-weight SMKIs have become an active research field in the discovery of kinase inhibitors. Targeting the human kinome has produced fruitful SMKIs for medical use. As of December 31, 2020, 63 SMKIs have been approved by the U.S. FDA (Figure 1), and several SMKIs, including icotinib (in China in 2011), apatinib (in China in 2014), anlotinib (in China in 2018), pyrotinib (in China in 2018), fruquintinib (in China in 2018), peficitinib (in Japan in 2019), flumatinib (in China in 2019), tirabrutinib (in Japan in 2020), almonertinib (in China in 2020), delgocitinib (in Japan in 2020), and filgotinib (in Japan and European Community in 2020), have been approved outside of the USA. In addition, a large number of SMKIs are currently in clinical trials. An online updated database named Protein Kinase Inhibitor Database (PKIDB) compiles SMKIs that have been in phase 0 to 4 clinical trials. Annotations extracted from seven public resources are supplied.(6) This database provides a good tool to analyze the SMKIs that are currently on the market or under development.
Figure 1
Figure 1. SMKIs approved by the U.S. FDA. The INNs of drugs (compounds 1–10) with indications other than cancer are displayed in magenta ellipsoids, and their chemical structures are shown.
Kinase deregulation plays essential roles in virtually all major disease areas. Accumulating evidence has revealed that kinases are promising drug targets for different diseases, including cancer, autoimmune diseases, inflammatory diseases, cardiovascular diseases, central nervous system (CNS) disorders, viral infections, and malaria. In 2001, the U.S. FDA approved the first SMKI, imatinib, and before 2011, the U.S. FDA approved nine SMKIs; however, these SMKIs were exclusively approved for cancer therapy. With the exception of 2016, breakthroughs have been made in the approval of SMKIs from 2011 to 2020: a few or several SMKIs were approved each year. In 2011, an SMKI named ruxolitinib (1), a JAK1 and JAK2 inhibitor, was approved for treatment of myelofibrosis, an indication different from cancer. This was the first SMKI approved for treatment of a nononcologic disease, which has brought a surge of interest in the development of SMKIs for both cancer and nononcologic diseases.(7) Indeed, after the approval of ruxolitinib, a total of 10 SMKIs have been approved by the U.S. FDA for indications other than cancer: ruxolitinib in 2011, tofacitinib (2) in 2012, ibrutinib (3) in 2013, nintedanib (4) in 2014, baricitinib (5), netarsudil (6), and midostaurin (7) in 2017, fostamatinib (8) in 2018, and upadacitinib (9)(8) and fedratinib (10)(9) in 2019 (Figure 1). These are significant achievements in kinase drug discovery. Table 1 summarizes the information on these 10 drugs. Among them, ibrutinib was first approved in 2013 for cancer therapy and was repurposed in 2017 and further approved for treatment of chronic graft versus host disease (GVHD), a medical complication that may occur after an allogeneic transplant.
| drug | target | company | approved year | indications for nononcologic diseases | indications for cancer | nononcologic diseases in clinical trials | cancer in clinical trials |
|---|---|---|---|---|---|---|---|
| ruxolitinib (1) | JAK1, JAK2 | Incyte Corp. | 2011 | myelofibrosis, PCV | PP, AA, atopic dermatitis, vitiligo, GVHD | diffuse LBCL, PTCL, pancreatic cancer, AML, glioblastoma, breast cancer, etc. | |
| tofacitinib (2) | Pan-JAK | Pfizer | 2012 | RA, PA, UC, AS, AA | vitiligo, atopic dermatitis, CD, dry eye syndromes, COVID-19, SLE | ||
| ibrutinib (3) | BTK | Pharmacyclics Inc. | 2017 (in 2013, it was approved for cancer first) | chronic GVHD | CLL, WM, MCL, marginal zone lymphoma | food allergy, COVID-19 | diffuse LBCL, small lymphocytic leukemia, gastroesophageal cancer, glioblastoma, lung cancer, etc. |
| nintedanib (4) | multi tyrosine kinases | Boehringer Ingelheim | 2014 | IPF, interstitial lung diseases | NSCLC | lung transplant recipients | bladder cancer, metastatic bowel cancer, liver cancer, brain tumor glioblastoma multiforme, ovarian cancer |
| baricitinib (5) | JAK1, JAK2 | Incyte Corp., Eli Lilly | 2017 | RA | AA, COVID-19, GVHD, juvenile idiopathic arthritis, lupus erythematosus, arteritis, atopic dermatitis, liver diseases, uveitis, primary biliary cholangitis, psoriasis, etc. | ||
| netarsudil (6) | ROCK1, ROCK2 | Aerie Pharmaceutical | 2017 | glaucoma, ocular hypertension | Fuchs’ endothelial dystrophy, cataract, bullous keratopathy, corneal edema | ||
| midostaurin (7) | multitarget kinases | Novartis | 2017 | systemic mastocytosis | AML, myelodysplastic syndrome | hepatic impairment | rectal cancer, leukemia |
| fostamatinib (8) | SYK | Rigel Pharmaceutical | 2018 | chronic ITP | renal transplant rejection, RA, warm antibody autoimmune hemolytic anemia, immune thrombocytopenic purpura | ovarian cancer, hematological malignancies, T-cell lymphoma | |
| upadacitinib (9) | JAK1 | Abbvie | 2019 | RA | atopic dermatitis, spondyloarthritis, juvenile idiopathic arthritis, AS, takayasu arteritis, UC, CD, SLE, giant cell arteritis, PA | ||
| fedratinib (10) | JAK2 | Celgene | 2019 | myelofibrosis | thrombocythemia, myelodysplastic syndrome, chronic beryllium disease, beryllium sensitization | AML |
a
Clinical information in this table was mainly obtained from the Web site of www.clinicaltrials.gov.
b
Abbreviations used in this table: AA, alopecia areata; AML, acute myeloid leukemia; AS, ankylosing spondylitis; CD, Crohn’s disease; CLL, chronic lymphocytic leukemia; COVID-19, coronavirus disease 2019; GVHD, graft versus host disease; IPF, idiopathic pulmonary fibrosis; ITP, immune thrombocytopenia; LBCL, large B-cell lymphoma; MCL, mantle cell lymphoma; NSCLC, Nonsmall cell lung cancer; PA, psoriatic arthritis; PCV, polycythemia vera; PP, plaque psoriasis; PTCL, peripheral T-cell lymphoma; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; UC, ulcerative colitis; WM, Waldenström’s macroglobulinemia.
SMKIs may selectively target one kinase, two kinases, or several kinases. For example, nintedanib (4), an SMKI indicated for idiopathic pulmonary fibrosis (IPF) and chronic fibrosing (scarring) interstitial lung diseases, inhibits fibroblast growth factor receptor 1–3, platelet-derived growth factor receptor (PDGFR) α and β, vascular endothelial growth factor receptor (VEGFR) 1–3, and FMS-like tyrosine kinase 3 (FLT3). Among these four kinase types, the first three are related to IPF pathogenesis. By binding competitively to the ATP-binding pockets of these kinases, this drug blocks the intracellular signaling pathways implicated in IPF pathology. Midostaurin (7) also targets multiple kinases, including FLT3. In both situations, the successes of these two drugs cannot be credited to a single kinase.
In addition to SMKIs, a few macrolides derived from the natural compound rapamycin that target a kinase named mammalian target of rapamycin (mTOR) were licensed for treatment of a few nononcologic diseases. The molecular weights of these macrolides are more than 900 Da, and thus, they are not considered typical SMKIs. In this Perspective, mTOR will be highlighted as a successful kinase target for the development of drugs for treatment of nononcologic diseases.
Aside from the human kinome, targeting kinomes of other species is an effective way to discover medicines to cure infectious diseases. In this field, the most striking example is the discovery of SMKIs for treatment of human malaria. However, no SMKIs targeting kinases not present in humans have been approved. This Perspective discusses a number of kinases present in human beings and other species and their small-molecule inhibitors for treatment of diseases in nononcologic therapeutic fields. In section 2, successful kinase inhibitors already approved for nononcologic diseases are discussed, and in section 3, potential kinase inhibitors that demonstrated efficacy in nononcologic disease models are presented. The opportunities and challenges in developing such SMKIs to meet unmet medical needs are highlighted in section 4.
2. Successful Kinase Inhibitors for Nononcologic Diseases
ARTICLE SECTIONS
2.1. Janus Kinase
Cytokines have indispensable roles in critical cellular functions, including survival, proliferation, inflammation, immunity, and invasion. Recently, there has been increasing interest in modulating the vital intracellular components of cytokine signaling, particularly the Janus kinase (JAK) family,(10) which belongs to a family of intracellular, nonreceptor tyrosine kinases. The JAK family includes four members, JAK1–3 and tyrosine kinase 2 (TYK2), all of which transmit cytokine-mediated signals via the JAK-STAT (signal transducers and activators of transcription) pathway (Figure 2).(11) This pathway influences DNA transcription. Researchers have revealed that JAK2V617F mutation is present in 50–60% of myelofibrosis patients and 95% of polycythemia vera (PCV) patients,(12) paving the way for the development of targeted therapies designed to inhibit overactive JAK signaling. JAK inhibitors have emerged as a feasible treatment option for inflammatory disorders and autoimmune diseases.
Figure 2
Figure 2. JAK/STAT signaling pathway. Various cytokines, such as interleukins, interferons, and neurotrophic factors, bind to their corresponding transmembrane receptors, leading to receptor dimerization. Then, JAKs are recruited to the intracellular region of receptors, resulting in the autophosphorylation of JAKs, which subsequently activates their respective STATs. STATs homodimerize/heterodimerize and then translocate into the nucleus to induce the transcription of various downstream targets associated with inflammation and cancer. IL, interleukin; IFN, interferon.
To date, five JAK inhibitors, ruxolitinib (1), tofacitinib (2), baricitinib (5), upadacitinib (9), and fedratinib (10), have been approved by the U.S. FDA for treatment of autoimmune diseases, inflammatory disorders, and dermatosis. Many other JAK inhibitors are in clinical trials. Oclacitinib, an analogue of tofacitinib, was approved by the U.S. FDA in 2013 as a veterinary medication. This drug is used for treatment of pruritus due to allergic dermatitis and atopic dermatitis in dogs more than 1 year old.
In 2011, the U.S. FDA approved ruxolitinib (1), a JAK inhibitor with selectivity for JAK1 and JAK2 subtypes, to treat intermediate- or high-risk myelofibrosis, and thus, ruxolitinib became the first SMKI with an indication outside of oncology. In 2014, this drug received another approval for PCV patients with an inadequate response to or intolerance for hydroxyurea. Additionally, ruxolitinib has been investigated for use in autoimmune diseases, including plaque psoriasis (PP), alopecia areata (AA), atopic dermatitis, vitiligo, and GVHD. A phase 2 clinical trial of ruxolitinib for PP demonstrated that topical ruxolitinib is effective, with a safe, well-tolerated profile.(13,14) A phase 2 clinical trial of ruxolitinib for AA showed that nine of 12 patients exhibited noteworthy responses to treatment, with no serious adverse effects and an average hair regrowth of more than 90% at the end of the treatment.(15) In the field of oncology, ruxolitinib has been investigated for use in several cancer types such as peripheral T-cell lymphoma (PTCL), diffuse large B-cell lymphoma (LBCL), pancreatic cancer, acute myeloid leukemia (AML), glioblastoma, and HER-2-positive breast cancer.
As a pan-JAK inhibitor, tofacitinib (2, CP-690550) inhibits JAK1–3 and TYK2, with Ki values of 0.7, 1.0, 0.2, and 4.4 nM, respectively.(16)Figure 3A shows the binding mode of tofacitinib to JAK3 (PDB 3LXK). This drug demonstrated excellent selectivity against a panel of more than 300 other kinases. Tofacitinib blocks the activity of interleukin (IL)-2, IL-4, IL-15, and IL-21 and interferes with the JAK-STAT signaling pathway. This drug was discovered and developed by the National Institutes of Health (NIH) of the U.S. government and Pfizer and approved by the U.S. FDA in 2012 to treat rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PA), and ulcerative colitis (UC). Currently, tofacitinib is being investigated in clinical trials for AA, vitiligo, and atopic dermatitis. In addition, tofacitinib has demonstrated potential for treatment of obesity because it is capable of converting white fat tissue into brown fat tissue, which is more metabolically active than white fat tissue.(17)
Figure 3
Figure 3. (A) Binding mode of tofacitinib to the ATP-binding site of JAK3 (PDB 3LXK). Tofacitinib forms two hydrogen bonds with Glu903 and Leu905. (B) Binding mode of BMS-986165 to TYK2 JH2 (PDB 6NZP). In addition to hydrophobic interactions, five hydrogen bonds between BMS-986165 and the Arg738, Lys642, Glu688, and Val690 residues can be observed.
Baricitinib (5), which shares the same chemical scaffold as ruxolitinib and was developed by Incyte and Eli Lilly, is an oral drug for treatment of RA.(18) Baricitinib selectively inhibits JAK1 and JAK2, with IC50 values of 5.9 and 5.7 nM, respectively. Baricitinib was approved in Europe in 2017 as a second-line therapy for treatment of moderate to severe active RA in adults. This drug can be used alone or in combination therapy. In 2018, baricitinib was approved by the U.S. FDA to treat moderate to severe active RA in adult patients who did not have a passable response to one or more tumor necrosis factor (TNF) antagonist therapies. In March 2020, baricitinib received a breakthrough therapy designation from the U.S. FDA to treat AA. Beginning in April 2020, this drug has been investigated to treat patients suffering from coronavirus disease 2019 (COVID-19) based on the fact that the anti-inflammatory activity of baricitinib is anticipated to act on the inflammatory cascade related to COVID-19. Currently, this drug is in clinical trials for many disorders other than cancer. Baricitinib did not demonstrate significant safety concerns during the first six months of treatment.(19)
Upadacitinib (9) was approved in 2019 in both the USA and Europe to treat adult patients with moderate to severe active RA. Upadacitinib is a second-generation JAK inhibitor that is selective for the JAK1 subtype (∼60-fold and >100-fold selective for JAK1 over JAK2 and JAK3, respectively). According to the Web site https://www.clinicaltrials.gov/, many clinical trials of this drug are being performed for treatment of different nononcologic diseases, including Crohn’s disease (CD), UC, atopic dermatitis, and PA.
Fedratinib (TG101209, 10) is a semiselective JAK2 inhibitor developed for treatment of myeloproliferative diseases, including myelofibrosis, and this drug is orally available. Having a unique chemical structure compared with other approved JAK inhibitors, fedratinib inhibits JAK2, JAK3, FLT3, and RET (a transmembrane receptor protein–tyrosine kinase) with IC50 values of 6, 169, 25, and 17 nM, respectively. At present, a number of clinical trials of fedratinib for treatment of AML and several nononcologic diseases are being performed. In addition, fedratinib received a priority review designation and an orphan drug designation from the U.S. FDA.
Peficitinib (11, Figure 4) is a pan-JAK inhibitor with IC50 values of 3.9, 5.0, 0.7, and 4.8 nM against JAK1–3 and TYK2, respectively. In 2019, Japan approved peficitinib for treatment of RA.(20) However, clinical trials of this drug for PP, transplant rejection, and UC were discontinued.
Figure 4
Figure 4. Chemical structures of peficitinib, delgocitinib (approved in Japan), and other JAK inhibitors in clinical trials for nononcologic diseases (compounds 13–26).
Delgocitinib (12, JTE-052) was developed by Japan Tobacco Inc. In human clinical trials, this drug was revealed to be effective and well tolerated. In January 2020, Japan approved it for treatment of atopic dermatitis. Delgocitinib is a pan-JAK inhibitor with IC50 values of 2.8, 2.6, 13, and 58 nM against JAK1–3 and TYK2, respectively.(21) A phase 2b clinical trial of this drug for chronic hand eczema was completed, but a phase 2 clinical trial for discoid lupus erythematosus was terminated.
Currently, many JAK inhibitors are in clinical trials for both cancer and several nononcologic diseases (Figure 4 and Table 2). Among these JAK inhibitors, cerdulatinib (13, PRT062070), momelotinib (20), pacritinib (21, SB1518), PF-06700841 (23), and TD-1473 (structure undisclosed) are dual or multikinase inhibitors; the remaining ones are specific selective JAK inhibitors. Indeed, compared with pan-JAK inhibitors, data already produced from clinical trials have shown that selective JAK inhibitors have better efficacy and fewer adverse effects because the different inhibition levels of JAKs lead to different cytokine profiles.(10) In August 2020, a selective JAK1 inhibitor, filgotinib (17), was rejected by the U.S. FDA to treat RA, and more clinical data were requested. However, soon after this rejection, filgotinib was approved by both Japan and the European Commission in September 2020. At the same time, positive topline results from a phase 2b/3 trial of filgotinib for moderate to severe active UC were announced by the developers. In China, a phase 1 clinical trial of CS12192 (26), a possible irreversible JAK inhibitor developed by Shenzhen Chipscreen Biosciences, is beginning for RA. This compound selectively inhibits JAK3 (IC50 = 11 nM) over JAK1, JAK2, and TYK2 and demonstrated good therapeutic results in models of adjuvant-induced arthritis and collagen-induced arthritis.(22) Interestingly, this drug has an IC50 value of 162 nM against TANK-binding kinase 1, which was found to play a role in RANKL-induced NF-κB (nuclear factor κ light-chain enhancer of activated B-cells) activation. This helps in making CS12192 superior to other JAK inhibitors in the prevention of bone loss-associated osteoclastogenesis.
Table 2. Clinical Status of JAK Inhibitors with Indications Other than Cancera
| drug | target | company | most advanced phase | indications of nononcologic diseases | indications of cancer |
|---|---|---|---|---|---|
| cerdulatinib (13, PRT062070) | SYK, pan-JAK | Portola Pharmaceuticals | phase 3 | vitiligo | PTCL, NHL, etc. |
| decernotinib (14, VX-509) | JAK3 | Vertex Pharmaceuticals | phase 3 | RA, drug–drug interaction | |
| PF-06651600 (15) | JAK3 | Pfizer | phase 3 | AA, CD, RA, UC, active nonsegmental vitiligo, impaired kidney function | |
| abrocitinib (16, PF-04965842) | JAK1 | Pfizer | phase 3 | hepatic impairment, atopic dermatitis, plaque psoriasis, eczema, etc. | |
| filgotinib (17) | JAK1 | Gilead, Galapagos NV | phase 3b | RA, CD, UC, AS, SS, COVID-19, PA | |
| gandotinib (18) | JAK2 | Eli Lilly | phase 2 | myeloproliferative neoplasms, PCV, essential thrombocythemia, myelofibrosis | |
| itacitinib (19) | JAK1 | Incyte Corporation | phase 3 | GVHD, PP, RA, cytokine release syndrome | Hodgkin lymphoma, leukemia, pancreatic cancer, NSCLC, etc. |
| momelotinib (20) | JAK1, JAK2, JAK3 | Ym Biosciences Australia | phase 3 | myelofibrosis, PCV, thrombocythemia | relapsed/refractory metastatic pancreatic ductal adenocarcinoma, NSCLC |
| pacritinib (21) | JAK2, FLT3 | Cell Therapeutics | phase 3 | myelofibrosis, GVHD, COVID-19 | Leukemias, colorectal cancer, NSCLC, AML, etc. |
| Solcitinib (22) | JAK1 | GlaxoSmithKline | phase 2 | SLE, psoriasis | |
| PF-06700841 (23) | TYK2, JAK1 | Pfizer | phase 2 | UC, CD, alopecia, psoriasis, active nonsegmental vitiligo, PA | |
| BMS-986165 (24) | TYK2 | Bristol-Myers Squibb | phase 3 | psoriasis, lupus, CD, UC, Crohn’s enteritis | |
| PF-06826647 (25) | TYK2 | Pfizer | phase 2 | PP, IBD, psoriasis, UC, acne inversa | |
| CS12192 (26) | JAK3 | Chipscreen Ltd., China | phase 1 | RA | |
| TD-1473 | pan-JAK | J&J/Theravance | phase 2 | CD, UC, IBD |
a
Abbreviations used in this table: AA, alopecia areata; AML, acute myeloid leukemia; AS, ankylosing spondylitis; CD, Crohn’s disease; COVID-19, coronavirus disease 2019; IBD, inflammatory bowel disease; GVHD, graft versus host disease; NHL, non-Hodgkin lymphoma; NSCLC, nonsmall cell lung cancer; PA, psoriatic arthritis; PCV, polycythemia vera; PP, plaque psoriasis; PTCL, peripheral T-cell lymphoma; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SS, Sjögren’s syndrome; UC, ulcerative colitis.
b
This drug was approved in Japan and Europe in September 2020.
In the active conformation, the ATP-binding pockets of the four subtypes of the JAK family are highly conserved, and thus first-generation JAK inhibitors target most JAKs. For example, tofacitinib and ruxolitinib lack subtype selectivity, affecting JAK1/JAK2/JAK3/TYK and JAK1/JAK2, respectively, which results in dose-limiting side effects, such as JAK2 inhibition-driven cytopenias.(23) Recently, novel purinone pan-JAK inhibitors were identified, which have potential for treatment of respiratory diseases via the inhalation route.(24) The best compound demonstrated good selectivity for the JAK family. In addition, in a lipopolysaccharide (LPS) model of airway inflammation treated via the intratracheal route, the best compound demonstrated efficacy, long lung retention time, and low systemic exposure. However, for a variety of autoimmune diseases, there is a great need to develop novel selective JAK inhibitors for safer, more effective, and more convenient treatments. Although this task is challenging, second-generation JAK inhibitors upadacitinib and fedratinib, which have high selectivity, were sent to the market in 2019. The following is another example of the discovery of selective second-generation JAK inhibitors. Vertex Pharmaceuticals screened their compound library against JAK3, and multiple scaffolds exhibiting good inhibitory activity against JAK3 were discovered. Optimization of one of the scaffolds led to the discovery of decernotinib (14), a potent and selective JAK3 inhibitor with a novel chemical structure.(25)
Another strategy for the development of selective JAK inhibitors is targeting possible allosteric sites. For instance, collective evidence has demonstrated that selective inhibition of TYK2 could be a novel promising therapeutic approach with an optimal benefit–safety balance to treat several autoimmune diseases. However, targeting the ATP-binding pocket of TYK2 to identify selective TYK2 inhibitors is very challenging because of the high sequence homology with the JAK family. Promisingly, the unique catalytically inactive pseudokinase domain (JH2) in the JAK family could provide an ideal “allosteric” site for selective TYK2 inhibitor discovery.(26,27) Researchers from Bristol-Myers Squibb recently disclosed the discovery of BMS-986165 (24) as the first JH2-targeting allosteric TYK2 inhibitor, which is undergoing phase 3 clinical trials for psoriasis.(28) This compound inhibits TYK2 JH2 (IC50 value of 0.5 nM) and did not demonstrate inhibitory activities against TYK2 JH1, JAK1, JAK2, or JAK3 at concentrations up to 10 μM. Figure 3B shows the binding mode of BMS-986165 to TYK2 JH2.
On the basis of the inspiring clinical results for already known JAK inhibitors, it is expected that a few will be approved sooner or later for treatment of several different diseases, including cancer. In light of the accumulated medicinal chemistry knowledge, it is also anticipated that more selective and safer JAK inhibitors will be identified in the near future, enter into clinical studies, and finally be sent to the market for a number of diseases.
2.2. Bruton’s Tyrosine Kinase
Bruton’s tyrosine kinase (BTK), which plays a crucial role in B-cell development, is a member of the TEC kinase family of tyrosine kinases. BTK plays key roles in oncogenic signaling and is decisive for survival and proliferation of leukemic cells in several B-cell malignancies (Figure 5), and small-molecule BTK inhibitors have shown excellent antitumor activities. Currently, there is considerable interest in BTK inhibitors as anticancer agents for both B-cell malignancies and solid tumors.(29) Three BTK inhibitors, ibrutinib (3), acalabrutinib (27), and zanubrutinib (28), have been approved by the U.S. FDA for treatment of multiple myeloma, lymphoma, and B-cell leukemia, among other cancer types.
Figure 5
Figure 5. Overview of BTK, SYK, PI3K/AKT/mTOR, MAPK, and related signaling pathways. SRC family kinases, such as Lyn in B/T cells or other cells, phosphorylate ITAM, which then recruits and activates SYK. SYK subsequently phosphorylates several substrates to activate various signaling pathways. SYK activates BTK-PLCγ, which then leads to activation of DAG-PKC and IP3-Ca2+, triggering MAPK signaling, AKT-mediated NF-κB signaling, and calcium mobilization. These pathways are associated with inflammation and cancer. PI3K/AKT/mTOR pathway: CD19, as a coreceptor of B- or T-cell receptors, is activated by Lyn, which then recruits and activates PI3K. PI3K generates PIP3, which recruits BTK and AKT. AKT activation by PDK1 and mTORC2 results in activation of mTORC2 and inhibition of GSK3. These downregulation targets are associated with inflammation, aging, neuropathy, and cancer. MAPK signaling includes the MKK4/7-JNK pathway, MKK3/4/6-p38 pathway, and MEK-ERK pathway. SYK activates the complex SLP65/GRB2/VAV/SOS, leading to activation of the MKK4/7-JNK pathway and MKK3/4/6-p38 pathway, which are associated with inflammation and cancer. PLC, phospholipase; DAG, diacyl glycerol; IP3, inositol triphosphate; IKK, IκB kinase; BCR/TCR, B/T-cell receptor; PIP2, phosphatidyl inositol 4,5-biphosphate; NFAT, nuclear factor of activated T-cells; ITAM, intracellular tyrosine activation; PDK1, 3-phosphoinositide dependent kinase-1; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; GRB2, growth factor receptor-bound protein 2.
In addition, increasing evidence suggests that BTK has multiple roles in mononuclear cells of the human innate immune system, particularly in macrophages and dendritic cells (DCs). This kinase was also recognized as a direct regulator of vital innate inflammatory machinery. BTK inhibitors likely have positive impacts on autoimmune diseases triggered by autoreactive B-cells and immune complex-driven inflammation.(30) Therefore, BTK has received much attention not only to obtain a more detailed understanding of the innate immune system but also to therapeutically modulate this system by developing medical agents. Indeed, BTK is a promising target for the development of drugs to treat various diseases involving B-cell and/or macrophage activation, not only limited to B-cell malignancies but also including several nononcologic diseases, such as RA, multiple sclerosis (MS), asthma, and systemic lupus erythematosus (SLE).(31)
Many BTK inhibitors have been reported.(32) On the basis of their binding mechanisms, BTK inhibitors are divided into reversible and irreversible (or covalent) inhibitors. These two types of inhibitors have their own benefits and different binding modes against BTK (see examples in Figure 6). The kinase domain of BTK contains Cys481 within the ATP-binding pocket in a position conserved in 11 kinases; therefore, Cys481 has been targeted for the development of selective covalent BTK inhibitors. All three BTK inhibitors approved by the U.S. FDA, ibrutinib (3), acalabrutinib (27), and zanubrutinib (28), are irreversible. Currently, many BTK inhibitors are in clinical trials to treat cancer and nononcologic diseases. Table 3 lists many BTK inhibitors with indications other than cancer. Most of them are covalent inhibitors.
Figure 6
Figure 6. (A) Irreversible binding mode of evobrutinib to BTK (PDB 6OMU). The covalent bond formed between Cys481 and evobrutinib is highlighted in purple. Evobrutinib forms three hydrogen bonds with the Thr474, Glu475, and Met477 residues. (B) Reversible binding mode of BMS-986142 to BTK (PDB 5T18). BMS-986142 forms two hydrogen bonds with Met477. For comparison, evobrutinib is depicted as a green stick model after superimposition of the X-ray crystal structure of 6OMU onto 5T18.
Table 3. Clinical Development Status of BTK Inhibitors for Nononcologic Diseasesa
| drug | applicants | status | indications for cancer | indications for nononcologic diseases |
|---|---|---|---|---|
| ibrutinib (3, PCI-32765) | Pharmacyclics Inc. | approved in 2013 | CLL, WM, MCL, marginal zone lymphoma | chronic GVHD |
| acalabrutinib (27, ACP-196) | Acerta Pharma | approved in 2017 | MCL, CLL, small lymphocytic lymphoma | RA (phase 2), post transplant lymphoproliferative disorder (phase 2), COVID-19 |
| zanubrutinib (28, BGB-3111) | BeiGene (Beijing) Co., Ltd. | approved in 2019 | MCL (approved) and several types of cancer in clinical trials | COVID-19 (phase 2) |
| rilzabrutinib (29, PRN1008) | Principia Biopharma | phase 3b | ITP, IgG4-related disease | |
| tolebrutinib (30, SAR442168) | Sanofi | phase 3b | MS | |
| evobrutinib (31) | Merck KGaA | phase 3b | MS, RA, SLE, impaired kidney function | |
| spebrutinib (32, CC-292, AVL-292) | Celgene Avilomics Research Inc. | phase 2b | Diffuse LBCL, CLL, B-Cell CLL, WM | RA |
| tirabrutinib (33, ONO/GS-4059) | Gilead Sciences | phase 2b,c | NHL, CLL | RA, SS |
| branebrutinib (34, BMS-986195) | BMS | phase 2d | RA, SS, SLE | |
| remibrutinib (35, LOU064) | Novartis | phase 2b | CSU, SS | |
| fenebrutinib (36, GDC-0853) | Genentech, Inc. | phase 2b | B-cell NHL, CLL | RA, SLE, lupus, CSU, urticaria |
| BMS-986142 (37) | BMS | phase 2b | RA, SS |
a
Abbreviations used in this table: CLL, chronic lymphocytic leukemia; COVID-19, coronavirus disease 2019; CSU, chronic spontaneous urticaria; ITP, immune thrombocytopenia; GVHD, graft versus host disease; LBCL, large B-cell lymphoma; MCL, mantle cell lymphoma; MS, multiple sclerosis; NHL, non-Hodgkin lymphoma; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SS, Sjögren’s syndrome; WM, Waldenström’s macroglobulinemia.
b
The most advanced phase.
c
This drug was approved in Japan in 2020 for primary central nervous system lymphoma, WM, and lymphoplasmacytic lymphoma.
d
It is recruiting for patients.
Ibrutinib (3), a potent irreversible BTK inhibitor, covalently targets Cys481 and presents very promising activity against B-cell malignancies.(33) Ibrutinib was developed for treatment of B-cell cancers, such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenström’s macroglobulinemia (WM). This drug was first approved by the U.S. FDA in 2013 and was repurposed in 2017 and further approved for use in chronic GVHD. As a first-generation BTK inhibitor, ibrutinib has exhibited side effects, including bleeding, rash, diarrhea, and atrial fibrillation, which are, in part, attributed to off-target kinase inhibitory-related effects on EGFR and other TEC family kinases.(34)
Acalabrutinib (27, ACP-196, Figure 7), which forms a covalent bond with Cys481 of the protein in the active site and was approved for treatment of MCL in 2017, demonstrated higher selectivity and more potent inhibition against BTK than ibrutinib and an improved safety profile with minimized adverse effects relative to ibrutinib.(35) Acalabrutinib is a second-generation, covalent BTK inhibitor. Currently, more than 55 clinical trials across 40 countries are underway or have been completed. Further studies to better understand and expand the therapeutic uses of acalabrutinib, either alone or in combination with other drugs, are being performed. Almost all of these clinical trials are for cancer, except two, which are for RA and posttransplant lymphoproliferative disorder. Both of these exceptions are in phase 2 clinical trials. The anti-inflammatory effects of BTK inhibitors have raised interest for COVID-19 treatment, and a study managed by the U.S. National Cancer Institute suggests that acalabrutinib may help reduce respiratory distress and inflammation in patients with COVID-19. Currently, AstraZeneca is conducting a 60-person randomized trial of acalabrutinib for COVID-19 treatment.
Figure 7
Figure 7. Chemical structures of BTK inhibitors approved (compounds 3, 27, and 28) or in clinical trials (compounds 29–37) for indications other than cancer.
Zanubrutinib (28, BGB-3111), another covalent BTK inhibitor, was approved by the U.S. FDA in November 2019 to treat MCL.(36) Many clinical trials of zanubrutinib for cancer are under way, and a phase 2 clinical trial for COVID-19 is recruiting patients as this Perspective is being written.
Rilzabrutinib (29, PRN1008) [WO 2014039899] is a covalent BTK inhibitor developed by Principia Biopharma and was acquired by Sanofi in September 2020. This compound is currently being evaluated in phase 3 clinical trials for persistent or chronic immune thrombocytopenia (ITP) and is in phase 2 trials for IgG4-related disease.
Tolebrutinib (30, SAR442168), originally developed by Principia Biopharma, is an investigational, oral, brain penetrant, selective small-molecule BTK inhibitor (with an IC50 value of 1.2 nM) [WO 2016196840]. In February 2020, Sanofi claimed that tolebrutinib met the primary endpoint of a phase 2 trial for relapsing MS. In this trial, tolebrutinib significantly reduced disease activity associated with MS as measured by magnetic resonance imaging. Tolebrutinib was well tolerated, with no new safety findings. This drug will potentially be the first disease-modifying therapy to address the source of MS damage in the brain. Sanofi then initiated four phase 3 clinical trials for relapsing and progressive forms of MS.
Evobrutinib (31) is a potent, covalent BTK inhibitor (IC50 = 8.9 nM) with higher kinase selectivity than EGFR and other TEC family kinases, indicating that it may be less likely to have adverse off-target effects.(37) This drug displayed suitable preclinical pharmacokinetic and promising pharmacodynamic characteristics. In addition, evobrutinib demonstrated efficacy in a rat model of RA. Currently, this drug is in clinical trials for a few autoimmune diseases, including SLE, MS, and RA. Figure 6A demonstrates the binding mode of evobrutinib to BTK.
Spebrutinib (32, CC-292, AVL-292), a highly selective, covalent BTK inhibitor, has been used in clinical trials to treat RA and diffuse LBCL, CLL, B-cell CLL, and WM.(38)
Tirabrutinib (33, ONO/GS-4059), a selective covalent BTK inhibitor, has been in phase 1/2 clinical trials for relapsed and refractory mature B-cell malignancies, RA, and Sjögren’s syndrome (SS).(39) In Japan, tirabrutinib was approved in 2020 for treatment of primary central nervous system lymphoma, WM, and lymphoplasmacytic lymphoma.
Branebrutinib (34, BMS-986195) is a covalent, irreversible BTK inhibitor targeting Cys481 that employs BMS-986142 as the lead compound.(40) Branebrutinib has an IC50 value of 0.10 nM against BTK and has a highly desirable selectivity profile with rapid target inactivation in vivo. With its preferable safety and tolerability profile, branebrutinib was sent into clinical evaluations for a few autoimmune disorders, such as RA and SS.
Remibrutinib (35, LOU064) is a potent, highly selective covalent BTK inhibitor developed by Novartis. Because it can bind to an inactive conformation of BTK, this drug displayed precise kinase selectivity.(41) In rat collagen-induced arthritis, remibrutinib demonstrated dose-dependent efficacy and potent in vivo target occupancy. At present, this drug is in phase 2 clinical trial evaluations for SS and chronic spontaneous urticaria (CSU).
Fenebrutinib (36, GDC-0853), currently in clinical development, is a highly potent (Ki = 0.91 nM), selective BTK inhibitor with a noncovalent binding mechanism.(42) Modified from GDC-0834,(43) this drug suppresses B-cell- and myeloid cell-mediated components of disease. In an in vivo rat model of inflammatory arthritis, fenebrutinib showed dose-dependent activity. As the most selective BTK inhibitor disclosed to date, fenebrutinib maintained its inhibitory activity against four different BTK mutants, including Cys481 and Thr474, which are in the active site and in the gatekeeper region, respectively. In ongoing preclinical studies and phase 2 evaluations in patients with several autoimmune disorders, including RA, SLE, urticaria, lupus, and CSU, fenebrutinib has shown highly favorable safety, pharmacokinetics, and pharmacodynamics profiles.(44) For a wide range of immunological disorders, this drug has the potential to become a best-in-class BTK inhibitor. In the field of cancer, phase 1 clinical trials of fenebrutinib have been completed for relapsed or refractory non-Hodgkin lymphoma (NHL) or CLL, and the results have shown generally well-tolerated antitumor activity.(45)
BMS-986142 (37) is a highly potent (IC50 = 0.50 nM), selective, and reversible BTK inhibitor based on carbazole and tetrahydrocarbazole.(46) Interestingly, this drug has two atropisomeric centers, which offer a single, stable atropisomer and lead to improved potency and selectivity as well as a reduction in safety liabilities. Figure 6B shows its binding mode to BTK. Currently, BMS-986142 has advanced into clinical phase 2 studies for RA and SS. Clinical results have indicated that at the doses tested, this drug is well tolerated. Once daily dosing is supported by its pharmacokinetic and pharmacodynamic profiles. In addition, this drug can be coadministered with methotrexate and does not have a pharmacokinetic interaction with methotrexate.(47)
More BTK inhibitors have been reported recently. RN486 (38, Figure 8), designed using structure-based methods, selectively inhibits BTK with an IC50 value of 0.3 nM and is a potential treatment for RA.(48) Compound 39, optimized based on a fragment hit, inhibits BTK with an IC50 value of 4 nM. In a rat model of collagen-induced arthritis, this compound reduced paw swelling in a dose- and exposure-dependent fashion.(49) Compound 40, identified by a scaffold-hopping approach, is a highly selective BTK inhibitor and demonstrated significant efficacy and good ADME and safety profiles in in vivo models; therefore, it was advanced into preclinical studies for RA treatment.(50) Compound 41 was discovered via a structure-hopping strategy from compound 39 and exhibited potent inhibitory effects against both BTKWT and BTKC481S (with IC50 values of 5.3 and 39 nM, respectively). In a rodent collagen-induced arthritis model, compound 41 effectively reduced paw swelling without body weight loss.(51)
Figure 8
Figure 8. Selected recently reported BTK inhibitors in preclinical studies.
For over a decade, many BTK inhibitors have been reported. Among them, three have been sent to the market, and many are in clinical trials for treatment of hematologic malignancies and chronic inflammatory disorders. We expect more BTK inhibitors will be approved for medical uses, especially in the fields of cancer and autoimmune diseases.
2.3. Rho-Associated Protein Kinase
As members of the protein kinase A, G, and C (AGC) family of serine-threonine kinases, rho-associated protein kinases (ROCKs) have critical roles in a wide range of cellular functions, including cell migration, cell contraction and actin organization, neurite elongation and neuronal architecture, angiogenesis, and cytokinesis.(52)Figure 9 shows the ROCK signaling pathway with downstream targets and direct biological regulation. ROCK has two isoforms, ROCK1 and ROCK2, which have 65%, 92%, and 100% identities in amino acid sequence, kinase domains, and ATP-binding pockets, respectively. The structural biology of ROCKs has demonstrated few differences between ROCK1 and ROCK2 at the biochemical and structural levels. ROCK1 and ROCK2 are ubiquitously expressed in most tissues; however, ROCK1 is preferentially enriched in non-nerve tissues, such as the liver, lung, kidney, spleen, and testis, whereas ROCK2 is mainly expressed in the heart and brain, indicating that these two different forms may have different biological activities and functions.
Figure 9
Figure 9. ROCK signaling pathway. As a GTPase, Rho is activated by guanine nucleotide exchange factors (GEFs). Together with GTP, Rho then activates ROCK to phosphorylate various substrates. Among its substrates, ERM, NHE1, adducin, CRMP2, NF-L, MLC, and MARCKS are associated with cellular responses and cytoskeletal regulation. LIMK is involved in the regulation of F-actin stabilization. GEF, guanine nucleotide exchange factors; ERM, ezrin-radixin-moesin; NHE1, sodium hydrogen exchanger 1; CRMP2, myosin light chain phosphatase 2; NF-L, neurofilament protein; MLC, myosin light chain; MLCP, myosin light chain phosphatase; MARCKS, myristylated alanine-rich C-kinase; LIMK, LIM kinases 1 and 2.
ROCK inhibitors may have potential medical applications in a wide range of pathological disorders, such as cancer, diabetes, intracerebral hemorrhage, neurodegenerative diseases (including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD)), pulmonary hypertension, Raynaud’s disease, diabetic retinopathy, and erectile dysfunction.(53) ROCK inhibitors are especially efficacious, alone or in combination with other ocular hypotensive agents, in lowering the intraocular pressure in patients suffering from glaucoma and ocular hypertension, representing a triumph in translational medical research.(54) ROCK inhibitors exhibit neuroprotective activity and even an antifibrotic effect that is beneficial for conventional glaucoma surgery.
Netarsudil (6, AR-13324, Figure 10A) is a novel ROCK/norepinephrine transporter inhibitor with a Ki value of 1 nM against ROCK1 and ROCK2.(55) In animal models, netarsudil engendered durable and considerable intraocular pressure reductions with satisfactory pharmacokinetic and ocular tolerability profiles. Netarsudil was approved in 2017 by the U.S. FDA to reduce elevated intraocular pressure in patients who suffer from open-angle glaucoma or ocular hypertension. Because it explicitly targets the conventional trabecular pathway of aqueous humor outflow, netarsudil is a novel glaucoma medication. Netarsudil has completed clinical trials for the prevention of bullous keratopathy and Fuchs’ endothelial dystrophy. A phase 2 clinical trial for corneal edema has not yet recruited patients.
Figure 10
Figure 10. (A) Chemical structures of ROCK inhibitors approved worldwide. (B) Binding mode of fasudil to ROCK2 (PDB 2F2U). In addition to hydrophobic interactions, three hydrogen bonds and an atypical hydrogen bond (CH···O═C) can be observed between fasudil and the Met172, Asn219, Asp232, and Glu170 residues.
Two ROCK inhibitors, fasudil (42, HA-1077) and ripasudil (43, Figure 10A), were approved for clinical use outside of the USA before the approval of netarsudil. Fasudil is a relatively weak selective ROCK inhibitor, with a Ki value of 0.33 μM against ROCK2.(53,56) As demonstrated in Figure 10B, fasudil binds to the ATP-binding pocket of ROCK2, with the isoquinoline nitrogen atom forming a hydrogen bond with hinge residue Met172 and the sulfonamide moiety pointing toward the catalytic loop.(57) In 1995, Japan and China approved fasudil for treatment of cerebral vasospasm and to ameliorate the cognitive decline that occurs in stroke patients. Additionally, fasudil was found to be efficacious for treatment of pulmonary arterial hypertension in normal mice and showed promise in improving memory, indicating that fasudil could potentially treat age-related or neurodegenerative memory loss. In addition, fasudil showed clinical efficacy as a therapeutic option for pulmonary arterial hypertension.(58) Currently, clinical trial studies of this drug are recruiting patients or are already underway for ALS, Raynaud’s phenomenon, heart failure, atherosclerosis, hypercholesterolemia, and carotid stenosis. A phase 3 clinical trial of combined intravitreal fasudil and bevacizumab for diabetic macular edema was completed in Iran.
Ripasudil, an analogue of fasudil developed from fasudil, is a highly selective and potent ROCK inhibitor (IC50 values of 51 and 19 nM against ROCK1 and ROCK2, respectively). After incorporation of a fluorine atom and chiral attachment of a methyl group in the chemical structure of fasudil, the pharmacological action of ripasudil was noticeably improved, and the ROCK inhibitory activity of ripasudil was much more potent and selective than that of fasudil. In 2014, ripasudil was first approved in Japan and is now being used to treat glaucoma and ocular hypertension.(59) At the time of writing this Perspective, patients are being recruited for a phase 2 clinical trial of ripasudil for treatment of Fuchs’ endothelial dystrophy. Furthermore, ripasudil is under clinical trial to study its ability to treat diabetic retinopathy. In cultured human cells, this drug was shown to promote corneal endothelial cell proliferation, and in a rabbit wound model, it was shown to promote endothelial regeneration and wound healing.(60) In addition, by attenuating activation of conjunctival fibroblasts, this drug has been demonstrated to prevent excessive scarring after glaucoma filtration surgery.(61)
Apart from these three worldwide approved ROCK inhibitors, many ROCK inhibitors have been disclosed. Among them, several have been reported to have potential clinical applications for nononcologic diseases, especially in the field of ophthalmology. In Table 4, six ROCK inhibitors (compounds 44–49) that are in clinical studies to treat several different nononcologic diseases are listed. Additionally, a ROCK inhibitor named AT13148 from Astex is in a phase 1 clinical trial for advanced solid tumors. Improvement of the isoform selectivity of ROCK inhibitors might have the advantage of fewer side effects, and such inhibitors could be applied for additional nononcologic diseases, such as CNS disorders, including AD.
Table 4. Clinical Development Status of ROCK Inhibitors for Treatment of Nononcologic Diseasesa
a
Abbreviations used in this table: GVHD, graft versus host disease; IPF, idiopathic pulmonary fibrosis.
Some ROCK inhibitors have demonstrated interesting biological activities. Fasudil and Y-27632 (44) enhanced osteoclastogenesis and accelerated bone healing in rat calvarial defects.(62) The ROCK inhibitors H1152, Y-27632, and fasudil can activate autophagy and proteasome pathways, suggesting that ROCK inhibitors represent a viable therapeutic route to reduce the pathogenic forms of tau protein in tauopathies, including AD.(63) A selective ROCK2 inhibitor, BA-1049 (50, Figure 11), is an encouraging treatment for cavernous angioma, which is a disorder without an existing treatment except surgical removal of brain lesions.(64) Compounds with the 4H-chromen-4-one scaffold were reported as ROCK inhibitors.(65) Among them, compound 51 showed excellent kinase selectivity for ROCK1 (IC50 = 14 nM) and ROCK2 (IC50 = 3 nM) against 387 other kinases. This compound inhibited endothelial cell migration in vitro and demonstrated an excellent ability to protect neuronal cells against high glucose-induced damage. In addition, in retinal explants, under the high glucose stress induced in retinal explant models of diabetic retinopathy, compound 51 promoted the regression of vascular vessels, indicating that compound 51 could be a potential lead compound for further study against diabetic retinopathy.
Figure 11
Figure 11. Chemical structure of BA-1049 and compound 51 discussed in the text.
2.4. Spleen Tyrosine Kinase
Spleen tyrosine kinase (SYK), also known as tyrosine protein kinase, is a member of the SYK family of tyrosine kinases. SYK is largely expressed in hematopoietic tissues and is also expressed in a range of other tissues. SYK shares a typical dual SH2 domain that is separated by a linker domain. SYK within B-cells and Zap-70 within T-cells transmit signals from B-cell and T-cell receptors, respectively.(66) In addition to having a crucial role in adaptive immune receptor signaling, SYK mediates various other biological functions, including innate immune recognition, cellular adhesion, osteoclast maturation, vascular development, and platelet activation. This kinase is linked to different inflammatory cells, such as macrophages, which are thought to be the cells responsible for ITP platelet clearance. Abnormal SYK function has been implicated in several instances of hematopoietic malignancies, indicating that SYK inhibition is helpful for treatment of B-cell malignancies. Moreover, SYK inhibition might be a safe and effective way to treat several different immunological diseases.
As the prodrug of the active compound tamatinib (52, R-406, Figure 12A), fostamatinib (8) was granted orphan drug status by the U.S. FDA. Tamatinib is an SYK inhibitor that binds to the ATP-binding pocket with an IC50 value of 41 nM.(67)Figure 12B demonstrates the binding mode of tamatinib to SYK (PDB 3FQS). Because of its ability to inhibit SYK, tamatinib reduces the destruction of platelets by the immune system, which permits an increase in platelet count and therefore decreases the probability of excessive bleeding. On the basis of positive results in a clinical trial program in 2018, fostamatinib was approved by the U.S. FDA to treat adult patients with chronic ITP.(68) This drug has been in clinical trial studies for autoimmune hemolytic anemia, RA, lymphoma, and immunoglobulin A nephropathy. With fostamatinib, an increase in blood pressure has been observed in the clinic, which can be attributed to the fact that tamatinib inhibits a wide range of kinases at higher concentrations.
Figure 12
Figure 12. (A) Structure of tamatinib (52, R-406) and its prodrug fostamatinib (8). (B) Binding mode of tamatinib to SYK (PDB 3FQS). In addition to hydrophobic interactions, two hydrogen bonds, and an atypical hydrogen bond (CH···O═C) can be observed between tamatinib and Ala451 and Glu449.
Very recently, to identify possible medical agents for the pandemic spread of SARS-CoV-2, fostamatinib was screened and repurposed as a candidate for treatment of acute lung injury and respiratory distress syndrome. In a mouse model of acute lung injury, mucin-1 abundance in lung epithelial cells was reduced after fostamatinib administration. In vitro, mucin-1 was removed from the cell surface by fostamatinib treatment. These results were first reported in bioRxiv.(69)
Currently, a number of SYK inhibitors have progressed into clinical evaluations. In addition to the compounds shown in Figure 13, a few SYK inhibitors, including HMPL-523 from Hutchison MediPharma Limited, which has an undisclosed structure, are in clinical trials for nononcologic disorders. HMPL-523 has completed a phase 1 clinical trial for RA, and patients are now being recruited for an ITP trial.
Figure 13
Figure 13. Chemical structures of SYK inhibitors in clinical trials or in trials already being terminated.
Two SYK inhibitors, entospletinib (53, GS-9973) and TAK-659 (54), and two dual SYK/JAK inhibitors, PRT062607 (55) and cerdulatinib (13), are currently being evaluated in the oncology setting.(70) The remaining compounds shown in Figure 13 are in clinical evaluations for patients with immunological disorders. Among them, MK-8457 (56) is a dual inhibitor of SYK and ZAP70 developed by Merck. This compound entered phase 2 clinical trials for RA.(71) However, because of serious infections, the trials were terminated. A phase 1 clinical trial of MK-8457 for blood pressure reduction in hypertensive participants has also been completed.
Entospletinib (53, GS-9973) is a selective SYK inhibitor. This drug is under clinical study for a few hematological malignancies.(72) Unfortunately, its development in inflammatory diseases was prevented by its interaction with proton pump inhibitors and a BID dosing regimen (the clinical trial for GVHD was terminated). As a second-generation selective SYK inhibitor, lanraplenib (57, GS-9876) was developed through modification of entospletinib. This compound has suitable pharmacokinetic properties for once daily administration. Moreover, lanraplenib has no interactions with proton pump inhibitors. At present, this drug has completed clinical evaluations for multiple autoimmune indications, including SLE (phase 2), lupus nephritis (phase 2), and SS (phase 2).(73) A phase 1 clinical trial of chronic GVHD was terminated. In addition, a few clinical trials for cancer, such as AML, have been terminated or are under way.
Gusacitinib (58, Asn002), an SYK inhibitor from Asana BioSciences, is currently in or has completed clinical trials for atopic dermatitis (phase 2), chronic hand eczema (phase 2), dermatitis eczema basal (phase 1), and basal cell nevus syndrome and basal cell carcinoma (phase 2).(74) Gusacitinib reversed the lesional skin transcriptome toward a nonlesional phenotype. In addition, this drug rapidly and significantly suppressed key inflammatory pathways implicated in atopic dermatitis pathogenesis. Therefore, gusacitinib might be an effective novel therapeutic agent for moderate to severe atopic dermatitis. Clinical trials for several cancer types were terminated, but one in adult sick persons suffering from low-risk nodular basal cell carcinoma is still underway (NCT02550678).
GSK2646264 (59) from GlaxoSmithKline is an SYK inhibitor that completed a phase 1 clinical trial for cutaneous lupus erythematosus and urticaria in 2019.(75)
SYK regulates amyloid-β production via Tau phosphorylation and NF-κB-dependent mechanisms by regulating the activation of glycogen synthase kinase 3β. SYK inhibition can interrupt Tau hyperphosphorylation, pathological amyloid-β accumulation, and neuroinflammation in AD. Therefore, SYK is a promising drug target to inhibit the development of the pathological lesions that define AD.(76) Nilvadipine (60), an L-type calcium channel antagonist used for treatment of hypertension and chronic major cerebral artery occlusion, inhibits SYK. This compound has been demonstrated to adjust Tau phosphorylation and amyloid-β production and thus has been suggested as a possible medication for AD.(76) At present, this compound is in phase 3 clinical trials for AD.
SYK has been validated as a target for the development of drugs to treat immunological diseases, and clinical and preclinical results have indicated that SYK inhibitors that are highly selective or can purposely tune broader inhibitory activity against many kinases are desirable.(77)
2.5. Mammalian Target of Rapamycin
In the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway, mammalian target of rapamycin (mTOR, also named mechanistic target of rapamycin) is a downstream effector (see Figure 5). The C-terminal domain of mTOR shares strong homology with the catalytic domain of PI3K; therefore, mTOR is recognized as a member of the PI3K-related kinase family. mTOR is ubiquitously expressed throughout the body and is the fundamental component of two distinct complexes, mTOR complex 1 (mTORC1) and mTORC2. As a serine/threonine protein kinase, mTOR regulates metabolism, cell growth, and protein synthesis in response to nutrients, growth factors, stress, and energy levels.(78)
Overactivation of mTOR signaling is related to tumor initiation and development, and mTOR activity has been found to be deregulated in many cancer types, such as lung, breast, prostate, brain, bladder, melanoma, and renal carcinomas.(79) mTOR inhibitors can be used as anticancer agents. Indeed, a few rapalogues (rapamycin and its analogues, not typical small molecules) have been approved as anticancer agents, and several small-molecule mTOR inhibitors, including sapanisertib and vistusertib, have been used in clinical studies for cancer treatment. In addition, mTOR is involved in age-related diseases, such as aging, cataracts, type 2 diabetes mellitus, cardiovascular diseases, and neurodegenerative diseases, for example, AD and ALS.(80)
The first-generation mTOR inhibitors are rapalogues. In clinical trials, such compounds have demonstrated antitumor activity against different tumor types.(81) By reducing sensitivity to IL-2 through mTOR inhibition, sirolimus (61, rapamycin, Figure 14A), a macrolide from bacteria, inhibits activation of B-cells and T-cells. Sirolimus is an allosteric inhibitor of mTORC1 and an autophagy inducer. Figure 14B shows the binding mode of sirolimus to mTOR (PDB 4DRH). The antiproliferative effects of sirolimus may play a role in cancer treatment, and this compound has been evaluated in more than 200 clinical trials for several cancer types, such as brain and CNS tumors, and has been approved for a number of cancer treatments. However, compared with control drugs, a higher rate of fatal adverse events has been found in cancer patients administered sirolimus, which is similar to findings related to its analogues, such as everolimus (62, RAD001) and temsirolimus (63, CCI-779, a prodrug of sirolimus).(82) Similar therapeutic effects have been found with other rapalogues; however, they have better hydrophilicity and can be administered orally and intravenously.
Figure 14
Figure 14. (A) Chemical structure of sirolimus and its analogues approved for medical uses. (B) Binding mode of sirolimus to mTOR (PDB 4DRH). Sirolimus forms extensive hydrophobic interactions with surrounding residues, and four hydrogen bonds between this drug and the Asp68, Gly84, Ile87, and Tyr113 residues can be observed.
In the field of nononcologic diseases, rapamycin has immunosuppressant functions in humans; therefore, it is particularly beneficial to prevent the rejection of kidney transplants and was approved in 2009 for the prevention of organ transplant rejection. Furthermore, in 2015, this drug was further approved to coat coronary stents and for treatment of lymphangioleiomyomatosis, a rare, progressive, and systemic disorder that characteristically leads to cystic lung destruction. In addition, sirolimus is used to treat venous malformations. Sirolimus has also shown promise in treating tuberous sclerosis, longevity, and neurodegenerative diseases, among others. In 2018, a phase 2 clinical trial named RAP-ALS with 63 ALS patients was started in Italy.(83)
From 2009 to 2016, everolimus (62) was approved by the U.S. FDA for several cancer types. This drug was further approved for the prevention of organ rejection after renal transplantation (in 2011) and liver transplantation (in 2013) and for tuberous sclerosis complex (TSC)-associated partial-onset seizures (in 2018).
Second-generation mTOR inhibitors are ATP-competitive inhibitors that act selectively on mTOR or on both mTOR and PI3K (dual PI3K/mTOR inhibitors). These two types of mTOR inhibitors have provided promising preclinical results in the field of oncology, and several such compounds, including apitolisib, dactolisib, gedatolisib, and sapanisertib, are in clinical trials for cancer treatment. At the same time, a few of them have been reported to be implicated in nononcologic diseases.
TSC is a disease with overactivated mTOR signaling. For seizure reduction in patients with TSC, clinical results of everolimus have revealed that mTOR inhibitors have therapeutic value in CNS disorders. Considering that everolimus is a partial inhibitor of mTOR function and starting from an in-house purine-based compound, scientists at Novartis developed a novel mTOR inhibitor (64, Figure 15) with enhanced properties that is appropriate for CNS disorders. This brain penetrant compound selectively targets mTOR, exhibited good brain exposure, and remarkedly improved the survival rate of mice with neuronal-specific ablation of the Tsc1 gene.(84)
Figure 15
Figure 15. Reported mTOR inhibitors demonstrating efficacy in nononcologic disease models.
CZ415 (65) is a highly potent, selective ATP-competitive mTOR inhibitor. In a semitherapeutic collagen-induced arthritis mouse model, this compound exhibited efficacy.(85) Chloroquine (66) is an antimalarial drug and autophagy inhibitor. This well-known drug has been studied as an antiviral agent to treat Kaposi sarcoma-associated herpesvirus (KSHV). Through inhibition of activation of the mTOR and p38 MAPK (mitogen-activated protein kinase) pathways with an IC50 value of 0.27 μM, this compound repressed the lytic replication of KSHV.(86) Chloroquine and hydroxychloroquine have recently been used in clinical studies for treatment of COVID-19. Chloroquine has a quinoline core, and many mTOR inhibitors contain this fragment.
Torin 1 (67) is a selective mTOR inhibitor. Torin 1 exhibited 1000-fold and 100-fold selectivity for mTOR over PI3K and 450 other protein kinases, respectively. At concentrations of 2 and 10 nM, this compound can inhibit the phosphorylation of mTORC1 and mTORC2 substrates in cells.(87) In a U87MG xenograft model, Torin 1 was effective at a dose of 20 mg/kg, and in tumor and peripheral tissues, this compound exhibited good pharmacodynamic inhibition of downstream effectors of mTOR. Recently, it was reported that Torin 1 can intervene in mTOR signaling in the insular cortex to alleviate neuropathic pain.(88) Torin 2 (68), which has improved stability and prolonged half-life in mouse microsomes, was obtained by simplifying Torin 1. Torin 2 has an EC50 value of 25 nM against mTOR and an IC50 value of 37.1 nM against mTORC1.(89) Preclinical studies of Torin 2 have been carried out for various cancer types. This compound has antimalarial activity and can inhibit the replenishment of parasitophorous vacuole membrane proteins in the Plasmodium liver stage.(90) P529 (69, Palomid 529) inhibits mTORC1 and mTORC2 simultaneously.(91) P529 demonstrated a good performance in prostate cancer and could enhance sensitization to radiotherapy and some drugs. No concerns for ocular or systemic toxicity were associated with subconjunctival injections of P529 to treat neovascular age-related macular degeneration.(92)
Rapalogues are selective allosteric mTORC1 inhibitors and are unable to inhibit mTORC2. mTOR inhibitors that simultaneously inhibit both mTORC1 and mTORC2, such as Torin 2 and P529, are expected to expand the therapeutic potential of mTORC inhibitors. Indeed, many selective mTOR inhibitors have been reported, but most, for example, onatasertib,(93) have been evaluated in a wide range of malignancies. Considering the importance of selective mTOR inhibition in other diseases, it is anticipated that more mTOR inhibitors will be explored to determine their potential in these fields.
3. Potential Kinase Inhibitors for Nononcologic Diseases
ARTICLE SECTIONS
3.1. Phosphoinositol 3-Kinases
Phosphatidylinositol 3-kinases (PI3Ks) are a family of lipid kinases that phosphorylate the 3-OH in the inositol ring of phosphoinositides and play vital roles in critical cellular functions, including cell growth, differentiation, proliferation, survival, migration, and intracellular trafficking.(94) PI3Ks have eight identified members, which are divided into class I, class II, and class III PI3Ks. On the basis of the type of regulatory subunit, class I PI3Ks, which are the most studied, are further subdivided into two subclasses: IA (including PI3Kα, β, and δ) and IB (PI3Kγ). PI3Kα and PI3Kβ are ubiquitously expressed, while PI3Kδ and PI3Kγ are expressed in epithelial cells, the hematopoietic system, and the CNS.
The PI3K pathway is one of the most extensively studied pathways for cancer therapeutics (see Figure 5).(95) All four class I PI3Ks are implicated in cancer.(96) Four drugs, idelalisib (a PI3Kδ inhibitor), copanlisib (a pan-PI3K inhibitor), duvelisib (a dual PI3Kδ/γ inhibitor), and alpelisib (a PI3Kα inhibitor), were approved in 2014, 2017, 2018, and 2019, respectively, for treatment of several cancer types.
Additionally, deregulation of the PI3K pathway has implications in many nononcologic diseases.(97) Increasing evidence has revealed that PI3Kα is related to obesity and diabetes, PI3Kβ is related to thrombosis, both PI3Kγ and PI3Kδ are related to RA and asthma, PI3Kδ is implicated in activated PI3Kδ syndrome (APDS), and PI3Kγ is implicated in IPF. Genetic inactivation of PI3Kα and PI3Kβ leads to embryonic lethality in mice. PI3Kγ and PI3Kδ have been identified as promising targets for the development of drugs to treat inflammatory diseases and immunomodulatory disorders.
To develop medical agents with adequate therapeutic indexes, specifically for nonlife-threatening diseases, PI3K inhibitors with good isoforms and wide kinase selectivity are of great interest. A wealth of effort by pharmaceutical companies and academic groups has been devoted to identifying novel isoform-selective, pan PI3K inhibitors, or dual (such as PI3K/HDAC and PI3K/mTOR) inhibitors, leading to four marketed anticancer drugs and at least 38 clinical candidates.(97) The primary indications of these candidates (for instance, umbralisib) are oncology but also include nononcologic diseases, such as chronic obstructive pulmonary disease (COPD)/asthma and primary immunodeficiency disease (Table 5). However, no PI3K inhibitors have yet been approved for indications other than cancer, although a few are in clinical trials. To date, dramatic successes have been achieved with selective PI3Kδ inhibitors.
Table 5. PI3K Inhibitors Currently in Clinical Trials for Nononcologic Diseasesa
| drug | target | applicants | most advanced phase | nononcologic diseases in clinical trials |
|---|---|---|---|---|
| nemiralisib (70, GSK2269557) | PI3Kδ | GlaxoSmithKline | phase 2 | COPD, asthma, APDS, lymphadenopathy, bronchiectasis |
| GSK2292767 (71) | PI3Kδ | GlaxoSmithKline | phase 1 | asthma |
| seletalisib (72) | PI3Kδ | UCB Celltech | phase 3 | APDS/PASLI, SS |
| leniosilib (73, CDZ173) | PI3Kδ | Novartis | phase 3 | primary immunodeficiency disease |
| RV-1729 (74) | PI3Kδ/γ | RespiVert | phase 1 | COPD/asthma |
| RV-6153 (75) | PI3Kδ/γ | RespiVert | phase 1 | COPD/asthma |
| AZD8154 | PI3Kδ/γ | AstraZeneca | phase 1 | asthma |
a
Abbreviations used in this table: APDS, activated PI3Kδ syndrome; COPD, chronic obstructive pulmonary disease; PASLI, p110 delta activating mutation causing senescent T-cells, lymphadenopathy and immunodeficiency; SS, Sjögren’s syndrome.
Nemiralisib (70, GSK2269557, Figure 16), developed by GlaxoSmithKline, is a selective PI3Kδ inhibitor currently in phase 2 for treatment of asthma, COPD, APDS, bronchiectasis, and PASLI (p110 δ activating mutation causing senescent T-cells, lymphadenopathy, and immunodeficiency).(98) Nemiralisib inhibits PI3Kδ, PI3Kα, PI3Kβ, and PI3Kγ , with IC50 values of 0.126, 5010, 1580, and 6310 nM, respectively. GSK2292767 (71), an analogue of GSK2269557, is a highly potent and selective PI3Kδ inhibitor that has excellent cellular activity.(98) GSK2292767 inhibits PI3Kδ, PI3Kα, PI3Kβ, and PI3Kγ, with IC50 values of 0.08, 500, 630, and 500 nM, respectively, and has been developed for asthma and COPD. In 2017, a phase 1 clinical trial of this compound in healthy smokers was completed. The selectivity of these two analogues toward PI3Kδ can be attained by taking advantage of the conformational flexibility and sequence diversity of the active site residues that have no contacts with ATP.(99)Figure 17A demonstrates the binding mode of nemiralisib to PI3Kδ (PDB 5AE8). Figure 17B shows that Thr750 (in yellow ball and stick mode), one of the key residues in PI3Kδ, determines the selectivity of nemiralisib and GSK2292767. In PI3Kα, PI3Kβ, and PI3Kγ, the residues corresponding to Thr750 are larger and positively charged (Arg770, Lys771, and Lys802), which would lead to clashes with nemiralisib and GSK2292767 when binding.
Figure 16
Figure 16. Chemical structures of PI3K inhibitors in clinical trials for nononcologic diseases.
Figure 17
Figure 17. (A) Binding mode of nemiralisib to PI3Kδ (PDB 5AE8). In addition to hydrophobic interactions, nemiralisib forms three hydrogen bonds with the Asp787, Glu826, and Val827 residues. (B) Key residues determining the selectivity of nemiralisib among PI3Kα, β, γ, and δ.
Seletalisib (72)(100) and leniosilib (73),(101) developed by UCB Celltech and Novartis, respectively, are two oral, selective PI3Kδ inhibitors. Both of these drugs have entered phase 3 clinical trials for APDS/PASLI and a phase 2 clinical trial for SS and have received orphan drug designations from the U.S. FDA.
Dual PI3Kδ/γ inhibitors are being developed for use in oncology and in respiratory diseases. RV-1729 (74) and RV-6153 (75) are two dual PI3Kδ/γ inhibitors from RespiVert Ltd. These two compounds have completed phase 1 clinical studies in respiratory diseases, asthma, and COPD. A phase 1 study has been initiated for another dual PI3Kδ/γ inhibitor, AZD8154 (structure not yet disclosed), for treatment of asthma.
Different selective PI3Kδ inhibitors have demonstrated similar adverse event profiles in clinical trials.(102) Thrombocytopenia, neutropenia, transaminitis, anemia, pneumonia/pneumonitis, and diarrhea/colitis are the most commonly observed adverse events. Dual PI3Kγ/δ inhibitors may have toxicity profiles similar to those of selective PI3Kδ inhibitors. However, selective PI3Kγ inhibitors may have a potentially favorable toxicity profile. Therefore, selective PI3Kγ inhibitors are of great interest for treatment of inflammation, autoimmune diseases, and cardiovascular diseases. However, because of the high sequence similarity between isoforms, selective PI3Kγ inhibitors are difficult to identify. Currently, a selective PI3Kγ inhibitor, IPI-549, is in a phase 1 trial for immuno-oncology;(103) no selective PI3Kγ inhibitors have yet been in clinical trials for nononcologic diseases.
Recently, some PI3K inhibitors with interesting biological effects in nononcologic disease models have been disclosed. Compound 76 (Figure 18), a pan-PI3K inhibitor, was reported to improve mouse lung function, slow the progression of pulmonary fibrosis, and have promising therapeutic potential for IPF treatment.(104) However, because of the benefits of selective PI3K inhibitors, great interest has been focused on developing novel and selective PI3K inhibitors. Compound 77 was reported as a selective brain penetrant PI3Kγ inhibitor and showed efficacy in murine experimental autoimmune encephalomyelitis.(105) LAS195319 (78) has an IC50 value of 0.5 nM and is a potent selective PI3Kδ inhibitor. This inhaled compound has been proposed for treatment of COPD and severe asthma.(106) Compound 79 is a potent, selective, and efficacious PI3Kδ inhibitor that demonstrated high efficacy in a mouse collagen-induced arthritis model.(107) Compound 80 has good PI3Kδ subtype selectivity, promising oral bioavailability, and inspiring in vivo efficacy for treatment of respiratory disease.(108) AM-8508 (81) is a potent, selective PI3Kδ inhibitor that is orally bioavailable. In a keyhole limpet hemocyanin study in rats, this compound exhibited promising efficacy.(109)
Figure 18
Figure 18. Chemical structures of recently reported PI3K inhibitors demonstrating interesting biological effects in nononcologic disease models.
In the near future, it is expected that more PI3K inhibitors, especially selective PI3Kδ inhibitors, will be approved and reach the market for treatment not only of cancer but also of nononcologic diseases, including arthritis, asthma, and COPD.
3.2. PI3K/AKT/mTOR Pathway
As one of the major cellular signaling pathways and a vital intracellular signaling pathway in regulating cell cycle, the PI3K/AKT/mTOR pathway directly participates in several cellular processes, such as proliferation, cell growth, metabolism, and angiogenesis (see Figure 5).(110) This pathway has been found to be dysregulated in many fatal diseases, such as cancer and metabolic, cardiovascular, and neurological disorders. In addition, this pathway is involved in the development of osteoarthritis, a complicated degenerative disease that affects whole joint tissue.(111) The PI3K/AKT/mTOR pathway is a promising therapeutic target for anticancer drug development. PI3K/AKT/mTOR signaling pathway inhibitors include single-component (PI3K inhibitors, AKT inhibitors and mTOR inhibitors) and dual inhibitors, such as dual PI3K/mTOR inhibitors.
Monotarget agents designed to act on individual targets (such as PI3K in the PI3K/AKT/mTOR pathway) are usually inadequate for multigenic diseases such as cancer. Combination therapy or multitarget agents are more effective than monotarget agents. However, combination therapy is limited by dose-limiting toxicities and drug–drug interactions. In addition, the cost of combination therapy is greater than that of a single agent. Dual or multitarget agents may overcome these drawbacks, with the advantages of avoiding the different metabolism, pharmacokinetics, and bioavailabilities of each component in combination therapy. The risk of possible drug–drug interactions would be avoided, and the dosing regimen would be greatly simplified to enhance compliance and therapeutic efficacy. Nevertheless, the critical challenge for dual or multitarget agents is how to design a drug with the desired balance of two (or more) activities in concert with optimizing the ADME-PK properties and safety profile.(112)
Dual PI3K/mTOR inhibitors may effectively prevent PI3K signaling cascade transduction, overcome feedback loops, and block PI3K-independent mTOR activation; hence, the discovery and development of dual PI3K/mTOR inhibitors would provide beneficial therapeutic intervention strategies in cancer treatment,(113) and many such dual inhibitors have been reported; for example, gedatolisib (PF-05212384) and PF-04691502 are in clinical trial studies for cancer treatment.(114)
A representative dual PI3K/mTOR inhibitor is omipalisib (82, GSK2126458, Figure 19A), which inhibits PI3Kα/β/γ/δ and mTORC1/2 at picomolar concentrations and has been in a phase 1 clinical trial for advanced solid tumors in combination therapy with trametinib (GSK1120212, a MEK inhibitor).(115)Figure 19B displays the binding mode of omipalisib to PI3Kγ. Both PI3Ks and mTOR play roles in the pathogenesis of IPF. Recently, omipalisib was repositioned from oncology to IPF, and an early clinical trial demonstrated that this drug was reasonably well tolerated and produced important downstream effects on key intracellular signaling in the fibrotic lung at tolerated doses, supporting further assessment of PI3K/mTOR inhibition as a novel medical intervention for IPF therapeutics.(116)
Figure 19
Figure 19. (A) Chemical structure of omipalisib (GSK2126458). (B) Binding mode of omipalisib to PI3Kγ (PDB 3L08). Two hydrogen bonds are formed between omipalisib and the Ser806 and Val882 residues. In addition, a bridged hydrogen bond and one atypical CH···O═C hydrogen bond can be observed.
To explore their potential clinical uses for both cancer and nononcologic diseases, dual PI3K/mTOR inhibitors with high potency, few side effects, and low toxicity are urgently needed. In addition, we need to further explore the PI3K/AKT/mTOR pathway for more medical applications. For example, it was reported that activated PI3K/AKT signaling with increased or reduced mTOR and GSK3β activity influences the wound repair process; therefore, dual PI3K/AKT inhibitors may have the potential to treat diabetic wound healing.(117) In diseases of pregnancy, the AKT/mTOR signaling pathway plays an important role in human fetoplacental vascular insulin resistance.(118) Proof of these concepts needs to be further explored by using PI3K/mTOR, PI3K/AKT, and AKT/mTOR dual inhibitors.
3.3. FMS-like Tyrosine Kinase 3
As a type III receptor tyrosine kinase, FMS-like tyrosine kinase 3 (FLT3) is mainly expressed in early hematopoietic progenitor cells, facilitating hematopoietic expansion. Once the FLT3 ligand, a member of a small family of hematopoietic growth factors, binds to FLT3, and FLT3 is autophosphorylated and activated, mediating downstream signaling pathways, such as RAS/MAPK, JAK/STAT5 and PI3K/AKT, to promote myeloid cell survival, proliferation, and differentiation (Figure 20).(119) FLT3 is frequently mutated in AML, and nearly 30% of AML patients exhibit FLT3 mutations; thus, inhibition of FLT3 is an effective strategy to treat AML.(120) FLT3 is also involved in the development and function of DCs, which regulate immune responses as the main antigen-presenting cells. DCs can induce activation of T cells associated with the immune response and drive T cell differentiation toward specific phenotypes by secreting several cytokines.(121) Drugs targeting FLT3 have the potential to treat psoriasis through interference with DCs. Moreover, the FLT3 ligand is highly expressed at the site of inflammation in human RA, promoting the inflammation process and increasing the likelihood of tissue destruction. Therefore, FLT3 has been regarded as a therapeutic target for inflammatory diseases, including RA.(122) In addition, the FLT3 ligand is expressed by hematopoietic cells at the site of nerve injury. One study showed that FLT3 activation induced by intrasciatic nerve injection of FLT3 ligand results in pain hypersensitivity, suggesting that FLT3 inhibition could be a potential strategy for relieving pain caused by nerve injury.(123)
Figure 20
Midostaurin (7), a semisynthetic derivative of staurosporine, is a multitarget kinase inhibitor that showed good potency over 15 kinases, with IC50 values less than 0.1 μM. The major kinase targets include FLT3, phosphoinositide-dependent protein kinase 1, vascular endothelial growth factor (VEGF), PDGFR, KIT proto-oncogene receptor tyrosine kinase, and kinase domain receptor.(124) Because of its activity against FLT3, it was evaluated in clinical trials for adult patients who were newly diagnosed with AML and showed an FLT3 genetic mutation. Interestingly, based on its KIT inhibitory activity, midostaurin was also approved for treatment of a nononcologic disease, advanced systemic mastocytosis, in which a KIT D816 mutation was found in approximately 90% of patients.(125) In addition, midostaurin has been evaluated for diabetes-related macular degeneration, supported by its inhibitory activity against VEGF and angiogenesis.(126)
SB1578 (83, Figure 21), a multikinase inhibitor targeting FLT3 (IC50 = 62 nM), JAK2 (IC50 = 46 nM), and colony-stimulating factor 1 receptor (CSF1R, IC50 = 69 nM), showed promising results via oral administration in a collagen-induced arthritis model and a rodent adjuvant-induced arthritis model of RA. SB1578 has entered phase 3 clinical trials for myelofibrosis, GVHD, COVID-19, and several cancer types. As discussed in section 2.1, JAK2 has an important role in regulating proinflammatory cytokine signaling associated with the pathogenesis of RA. CSF1R is a tyrosine kinase receptor, and its expression is increased in pathologies of RA. Therefore, simultaneous blockade of these three kinases could be an effective strategy for RA treatment. SB1578 was designed by optimizing the structure of SB1518 (a JAK2/FLT3/TYK2 inhibitor, pacritinib, 21) and SB1317 (84, a CDK/JAK2/FLT3 inhibitor) to achieve improved solubility and selectivity over CDK, which plays a critical role in oncology applications.(127) SB1578 demonstrated potent oral efficacy in a murine collagen-induced arthritis model of RA, supporting the notion that SB1578 could be a potential method for treatment of autoimmune diseases and inflammatory disorders such as psoriasis and RA. SB1578 reached phase 1 clinical trials in healthy volunteers in 2010, but no advanced clinical trials are available to date.
Figure 21
Figure 21. Chemical structures of a few FLT3 inhibitors discussed in the text.
A series of 1-(4-((1H-pyrazolo[3,4-d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-3-(5-(tertbutyl)isoxazol-3-yl)urea derivatives have been reported as FLT3 inhibitors for psoriasis treatment.(128) Previously, this series of compounds, for example, compound 85, were dual FLT3/VEGFR2 inhibitors used for AML, but they also exhibited certain antipsoriatic effects in K14-VEGF transgenic homozygous mice.(129) On the basis of compound 85, a potent FLT3 inhibitor (compound 86, IC50 = 6 nM against FLT3) was discovered and found to exhibit significant antipsoriatic activity in a K14-VEGF transgenic mouse model. After the last administration, there was no recurrence in mice 15 days later. In vitro experiments indicated that compound 86 could reduce DC products and inhibit cytokine secretion by DCs by blocking the FLT3 signaling pathway. Therefore, the authors suggested that compound 86 might be a candidate for psoriasis treatment.
SKLB4771 (87) is a potent FLT3 inhibitor (IC50 = 10 nM) with good kinase spectrum selectivity.(130) When used for psoriasis-like symptoms of disease in mice, this compound almost completely cured this disease without obvious toxicity. Studies have demonstrated that SKLB4771 leads to a significant decrease in pDC and mDC levels and activation both in vitro and in vivo. In addition, subsequent T-cell cascade reactions regulated by Th1/Th17 pathways were also reduced. These results revealed that specific targeting of FLT3, or hence direct interference with DCs, may be a novel strategy for psoriasis treatment.
3.4. Apoptosis Signal-Regulating Kinase 1
As a serine/threonine kinase and a part of the MAPK pathway, apoptosis signal-regulating kinase 1 (ASK1, also named mitogen-activated protein kinase 5) belongs to the mitogen-activated protein kinase kinase kinase (MAP3K) family.(131) Through phosphorylation and activation of downstream MAP2Ks, ASK1 activates the c-Jun N-terminal kinase (JNK) and p38 MAPK signaling cascades in response to different stressors, including saturated free fatty acids, TNF-α, and lipopolysaccharide (Figure 22). ASK1 is known to regulate cell proliferation. Inhibition of ASK1 results in decreased activation of hepatic macrophages and protects against both hepatic inflammation and fibrogenesis. Several lines of evidence have indicated that aberrant ASK1 signaling leads to several human diseases, such as cancer, cardiovascular disease, diabetes, RA, nonalcoholic fatty liver disease, neurodegenerative disease, infections, and MS.(132,133)
Figure 22
Figure 22. Role of ASK1 in the MKK4/7-JNK and MKK3/4/6-p38 signaling pathways. ASK1 is activated by inflammatory cytokine signaling and oxidative stress, which then leads to activation of MKK4/7 and MKK3/4/6, triggering the JNK and p38 signaling pathways. RTKs, receptor tyrosine kinases; TRADD, tumor necrosis factor receptor-associated death protein; Daxx, death domain-associated protein; TRAF2, TNF receptor-associated factor 2.
ASK1 was identified as a promising target for therapeutic applications; therefore, much attention has been given to the development of ASK1 inhibitors, and many ASK1 inhibitors have been reported.(134) Among them, selonsertib (88, GS-4997, Figure 23) has advanced into phase 2 clinical trials for alcoholic hepatitis, diabetic kidney disease, nonalcoholic steatohepatitis, pulmonary arterial hypertension, and nonalcoholic fatty liver disease and demonstrated positive results, alone or in combination with other drugs.(135−138)
Figure 23
Figure 23. Chemical structures of reported ASK1 inhibitors discussed in the text.
On the basis of selonsertib, a combined structure-based and compound deconstruction approach was employed, and a novel series of potent ASK1 inhibitors with ideal physiochemical properties and efficiencies were rapidly produced.(139) The best compound, 89, was shown to reduce infarct size in the Langendorff perfused ex vivo heart model.
An X-ray cocrystal structure of selonsertib binding to ASK1 was published (Figure 24, PDB 6OYT), and structural analysis resulted in the design and synthesis of many novel macrocyclic inhibitors following a deconstruction–cyclization approach.(140) Compound 90 showed good cellular potency and pharmacokinetic properties with excellent brain exposure. The authors claim that these ASK1 inhibitors might be useful tools to further understand the role of ASK1 inhibition in neurodegenerative disease.
Figure 24
Figure 24. Binding mode of selonsertib to ASK1 (PDB 6OYT). Selonsertib forms two hydrogen bonds with Lys709 and Val757. In addition, it has extensive hydrophobic interactions with surrounding residues, including Leu686, Val694, Ala707, Met754, Val757, and Leu810.
More brain penetrant ASK1 inhibitors have been reported. MSC2032964A (91) selectively inhibits ASK1 with an IC50 value of 90 nM. It was tested in an in vivo autoimmune encephalomyelitis model (an animal model of MS) and found to attenuate the severity of encephalomyelitis without affecting the proliferation capability of T-cells, suggesting that the TLR-ASK1-p38 pathway in glial cells might be a promising drug target for autoimmune demyelinating diseases, such as MS.(141) K812 (92), is a specific ASK1 inhibitor (IC50 = 6 nM) that prolonged survival of transgenic mice with ALS, a fatal neurodegenerative disease.(142) K812 alleviates ALS disease progression by inhibiting activation of ASK1 in the spinal cord. GS-444217 (93), a selective, orally available ASK1 inhibitor, dose-dependently reduced pulmonary arterial pressure in animal models.(143)
3.5. Receptor Interacting Protein Kinases
Receptor interacting protein kinases (RIPKs) are a group of serine/threonine protein kinases. This family has seven members, RIPK1–RIPK7, all of which share a fairly conserved kinase domain but have diverse nonkinase regions and have emerged as essential sensors of intracellular and extracellular stresses.(144) RIPKs have vital roles in inflammation, other immune responses, and cell death-inducing processes.(145,146) As central inducers of necroptosis and apoptosis activation via caspase interactions, both RIPK1 and RIPK3 play well-established roles.(147) RIPK2 has been recognized as a valid therapeutic target to develop medical agents to treat a variety of autoimmune diseases. RIPK4 is less well studied but was identified as the causative gene in popliteal pterygium syndrome, an inherited disease affecting the face, limbs, and genitalia.(148) RIPK6 and RIPK7 (also named leucine-rich repeat kinase 1 and leucine-rich repeat kinase 2, respectively) have been associated with the pathogenesis of PD (see section 3.12).
3.5.1. Receptor Interacting Protein 1 Kinase
RIPK1 is a vital upstream regulator of inflammation and necroptosis, and the association of RIPK1 with various pathologies, including inflammatory, ischemic injury, neurodegenerative, and oncogenic diseases, has been studied.(149) RIPK1 is an inspiring therapeutic target for the development of drugs to treat inflammatory and neurodegenerative diseases, which are significant unmet medical needs. Currently, the RIPK1 inhibitor GSK2982772 (94, Figure 25) is undergoing phase 2a clinical trials in psoriasis, UC, and RA. This drug is ATP-competitive (IC50 value being 1.0 nM); however, it has a specific binding mode (Figure 26), which suggests that it is an allosteric inhibitor (type III class).(150) Because of this type III binding mode, GSK2982772 exhibits excellent kinome selectivity–monokinase selectivity: it only inhibits RIPK1 at a concentration of 10 μM against 456 kinases. On the basis of GSK2982772 and an HTS hit, compound 95, a highly potent, orally available, and brain penetrant RIPK1 inhibitor, was discovered.(151) In both mouse and human cells, this compound strikingly suppressed necroptotic cell death. In a mouse experimental autoimmune encephalomyelitis model of MS, oral administration of compound 95 attenuated disease progression.
Figure 25
Figure 25. Chemical structures of four reported selective RIPK1 inhibitors.
Figure 26
Figure 26. Binding mode of GSK2982772 to RIPK1 (PDB 5TX5). One hydrogen bond and a bridged hydrogen bond can be observed between GSK2982772 and the Asp156 and Val76 residues. GSK2982772 has extensive hydrophobic interactions with Val31, Ile43, Lys45, Met67, Leu70, Val75, Val76, Leu78, Leu90, Met92, Leu129, Val134, and Phe162.
DNL747, a RIPK1 inhibitor whose chemical structure has not yet been disclosed, is in clinical trials by Denali Therapeutics. DNL747 is brain penetrant and was found to be safe and well tolerated in two clinical studies in patients with ALS and AD. However, a higher dose is needed for desired effectiveness, which leads to chronic toxicity. Denali Therapeutics announced a pause clinical in testing of DNL747 and planned to start clinical studies in 2021 on DNL788, an alternative compound with a superior profile.
GNE684 (96) is a potent cross-species RIPK1 inhibitor. In one study, it lessened collagen antibody-induced arthritis; moreover, this compound prevented skin inflammation triggered by mutation of Sharpin and colitis triggered by deletion of Nemo from intestinal epithelial cells.(152) Compound 97 is a potent and highly selective (monokinase selectivity) RIPK1 inhibitor with a core of dihydropyrazole. This compound displayed effectiveness in human retinitis pigmentosa and mouse models of MS.(153)
RIPK1 is a checkpoint kinase governing tumor immunity. RIPK1 inhibitors have broad applications in the field of cancer. GSK3145095, a RIPK1 inhibitor whose chemical structure is related to GSK2982772, was recently reported,(154) and currently, this compound is in phase 1 clinical trials for treatment of pancreatic adenocarcinoma, as well as other solid tumors.
3.5.2. Receptor Interacting Protein 2 Kinase
Nucleotide oligomerization domain 1 (NOD1) and NOD2 are members of the NOD-like receptor family of innate immune proteins. This pathway is implicated in many different inflammatory disorders, such as Blau syndrome, RA, inflammatory bowel disease (IBD), sarcoidosis, and asthma.(155,156) RIPK2 is a multidomain, dual specificity kinase that is ubiquitously expressed. This kinase is the convergence point for NOD1 and NOD2 signaling and has been recognized as a valid drug target for developing medical agents for a variety of autoimmune diseases.(157)
GlaxoSmithKline recently described their efforts to develop selective RIPK2 inhibitors for the purpose of treating inflammatory disorders. GSK583 (98, Figure 27) was identified and pharmacologically characterized as a highly potent 4-aminoquinoline-based RIPK2 inhibitor and a tool compound that demonstrated efficacy in inhibiting downstream NOD2 signaling in different models, including cellular models, in vivo rodent models, and ex vivo human disease models.(158) Modification of GSK583 led to the discovery of another 4-aminoquinoline-based PIPK2 inhibitor 99, which possesses higher binding affinity against PIPK2, improved PK/PD profiles, and reduced hERG ion channel activity.(159) Further optimization of 99 led to 100, which has a 4-aminoquinazoline scaffold and demonstrated good cell-based activity in human whole blood and an excellent kinase selectivity profile. However, this compound has unacceptable solubility, and thus its phosphate ester prodrug 101, with a desired pharmacokinetic profile, was developed. This prodrug exhibited effectiveness in a murine IBD disease model and in a CD and UC explant assay by blocking spontaneous cytokine release; therefore, 101 was advanced into phase 1 clinical trials in 2018.(160) Compound 102, a selective and potent RIPK2 inhibitor with a bridged bicyclic pyrazolcarboxamide scaffold, was identified through fragment-based screening and optimization. This compound will allow investigation of RIPK2 as a therapeutic target for autoinflammatory disorders.(161)
Figure 27
Figure 27. Chemical structures of six reported selective RIPK2 inhibitors.
By employing virtual library screening and a structure-based design strategy, Novartis discovered the potent selective RIPK2 inhibitor 103, which has outstanding oral bioavailability.(162) In both cellular and in vivo models, this RIPK2 inhibitor dramatically decreased proinflammatory cytokine secretion.
Cocrystallization of compound 100 with RIPK2 confirmed a type I binding mode within the ATP-binding pocket of RIPK2, as demonstrated in Figure 28 (PDB 6RNA).
Figure 28
Figure 28. Binding mode of compound 100 to RIPK2 (PDB 6RNA). Three hydrogen bonds can be observed between 100 and Ser25, Met98, and Asp164. An atypical CH···O═C hydrogen bond can be found between 100 and Met98. Additionally, 100 has extensive hydrophobic interactions with Leu24, Ala45, Lys47, Leu70, Leu79, Ile93, Tyr97, Met98, Leu153, and Ala163.
3.6. Interleukin-1 Receptor-Associated Kinase 4
As crucial sensors of innate immunity and transmembrane pattern recognition receptors, the interleukin-1 receptor family and Toll-like receptor (TLR) family recognize pathogens and initiate signaling cascades to mount immune responses. Dysregulation of TLR signaling is particularly implicated in autoinflammatory diseases, such as RA, SLE, IBD, psoriasis, and gout.
Interleukin-1 receptor-associated kinase 4 (IRAK4), a serine/threonine protein kinase, is one of the four members of the IRAK family. This kinase supports signaling from T-cell receptors and takes part in innate immune response signaling from TLRs (Figure 29). As a critical component in an animal’s response to IL-1, IRAK4 deficiency in animals led to loss of the ability to recognize bacterial and viral invaders.(163) Adults deficient in IRAK4 do not have a significant increase in the risk of serious infections. IRAK4 is critical for protective immunity against numerous pathogens in animals but is largely redundant for protective immunity in humans. Intrinsic differences between animals and humans, affecting receptors other than TLRs, may account for the observed discrepancies.(164) In view of IRAK4’s position in several signaling events, IRAK4 has been considered a critical therapeutic target for a few inflammatory diseases, such as RA, IBD, and other autoimmune diseases.(165) Combined with other robust data, it is suggested that IRAK4 inhibition has the capacity to treat lupus.(166) In the field of cancer, the IRAK4 gene may have a role in the development of prostate cancer. IRAK4 inhibitors are novel agents designed to suppress immune signaling pathways, and therefore, selective IRAK4 inhibitors have their own specific advantages for medical use, such as avoiding broad immunosuppression. To date, many IRAK4 inhibitors have been disclosed, and among them, a few are in clinical trials for autoimmune diseases and hematological malignancies.(165)
Figure 29
Figure 29. Role of IRAK4 in the MKK3/4/6-p38 and MKK4/7-JNK signaling pathways. Once ligands such as LPS and IL-1 bind to the IL-1 receptor (IL-1R) and Toll-like receptors (TLRs), respectively, IRAK4 is recruited and activated by the adaptor protein MyD88. IRAK4 then activates IRAK1-TRAF6, stimulating the NF-κB, JNK and p38 pathways. In addition, IRAK1 activates IRAK2 to regulate the expression of caspase-8. FADD, Fas-associating protein with a novel death domain; Casp-8, caspase-8.
PF-06650833 (104, Figure 30) inhibits IRAK4 with an IC50 value of 0.2 nM. Its binding mode with IRAK4 is shown in Figure 31. This highly potent IRAK4 inhibitor was identified through a fragment-based drug discovery effort.(167) It has completed a phase 2 clinical trial for RA, and new patients are being recruited for a phase 2 clinical trial for hidradentis suppurativa, a long-term skin disorder characterized by the appearance of swollen and inflamed lumps. BAY1834845 (105) and BAY1830839, developed by Bayer, are two IRAK4 inhibitors (IC50 values of 3.4 and 3 nM, respectively). BAY1834845 has completed a phase 1 clinical trial for pelvic inflammatory disease. A phase 1/2 trial study was started in patients with RA or psoriasis in 2018. BAY1830839 (structure undisclosed) has completed a single ascending dose study in healthy volunteers for RA. CA-4948 (106) is 500-fold more selective for IRAK4 than IRAK1 and simultaneously inhibits FLT3. This compound demonstrated antitumor activity in animal models, and patients are currently being recruited for phase 1 clinical trials to study its potential to treat myelodysplastic syndrome, AML, and relapsed and refractory hematologic malignancies.
Figure 30
Figure 30. Chemical structures of IRAK4 inhibitors in clinical trials (A) and recently reported (B).
Figure 31
Figure 31. Binding mode of PF-06650833 to IRAK4 (PDB 5UIU). PF-06650833 forms three hydrogen bonds with Val263, Met265, and Ser328 and two bridged hydrogen bonds with Lys213 and Ser269.
Identification of novel selective IRAK4 inhibitors remains of significant interest. For example, ND-2110 (107) and ND-2158 (108), identified by Nimbus Therapeutics, have a cyclopenta[4,5]thieno[2,3-d]pyrimidine core and are highly potent (IC50 values of 7.5 and 1.3 nM), selective, and bioavailable IRAK4 inhibitors.(168) In mouse models, these two compounds demonstrated potential efficacy in alleviating collagen-induced arthritis, suppressing LPS-induced TNF production, and blocking gout formation. These discoveries suggest that IRAK4 inhibition could be a useful therapeutic strategy in a genetically defined population of activated B-cell-like subtypes of diffuse LBCL, autoimmune disorders, and other malignancies that are dependent on aberrant MYD88 signaling. Following this, AstraZeneca developed pyrrolopyrimidine- and 5-azaquinazoline-based IRAK4 inhibitors for oral treatment of mutant MYD88L265P diffuse LBCL.(169,170)
Nicotinamide-based compound 109 is a highly selective and potent IRAK4 inhibitor (IC50 = 3.4 nM) developed by Bristol-Myers Squibb.(171) In a lipoteichoic acid-induced acute inflammation model, at a 10 mg/kg dose, this compound offered a strong PD effect with >90% inhibition. BMS-986126 (110), structurally related to 109, is a potent, highly selective IRAK4 inhibitor. Both in vitro and in vivo, BMS-986126 exhibited equivalent activity against several MYD88-dependent responses. Through modification of their previously reported dihydrobenzofuran IRAK4 inhibitors, scientists at Genentech, Inc. discovered benzolactam-selective IRAK4 inhibitors, such as 111 (IC50 = 1.4 nM). In a TLR-challenged mouse model, this IRAK4 inhibitor demonstrated strong inhibition against multiple cytokines of interest and therefore is a useful tool compound for more in vivo experiments across different disease models.(172)
3.7. Glycogen Synthase Kinase 3
As a serine/threonine protein kinase, glycogen synthase kinase 3 (GSK3) has been acknowledged as a kinase involved in many central intracellular signaling pathways, such as apoptosis, migration, glucose regulation, and cell proliferation (Figure 32).(173) GSK3 has two isoforms: GSK3α and GSK3β. In resting cells, both isoforms are constitutively active; however, they have dissimilar tissue expression. GSK3 was initially identified in the context of its participation in regulating glycogen synthase. As one of a number of signaling components downstream from the insulin receptor, GSK3 is implicated in other aspects of glucose homeostasis. In addition, GSK3 has been shown to regulate immune and migratory processes and is fundamentally involved in several pathways associated with apoptosis and cell proliferation. By relocating a phosphate moiety from ATP to a serine residue of a protein substrate, GSK3β catalyzes hyperphosphorylation of tau protein and causes the formation of toxic insoluble neurofibrillary tangles. Therefore, because GSK3 is implicated in many diseases, including cancer, type 2 diabetes, neurodegenerative and psychiatric disorders, inflammation, bipolar disorder, bone density improvement, and ALS, it has received great interest as a research subject.(174) Indeed, many chemically diverse classes of GSK3 inhibitors, including metal cations, ATP-competitive inhibitors, non-ATP-competitive inhibitors, natural products, and substrate-competitive inhibitors, have been reported and are being tested for therapeutic usage.(174) Among them, two are under clinical investigation for various disorders.
Figure 32
Figure 32. GSK3 signaling pathway. GSK3 can be activated by PI3K signaling, regulating protein synthesis and glycogen synthesis. Binding of WNT to Frizzled and LRP5/6 complex results in recruitment and activation of Dsh protein, which then inhibits a protein complex containing GSK3, AXIN, APC, CKII, and β-catenin, blocking the phosphorylation and consequent degradation of β-catenin. Once D2 receptor activation occurs, β-arrestin brings AKT and GSK3 to PP2A. PP2A dephosphorylates AKT and GSK3, deactivating AKT and activating GSK3. LRP5/6, LDL receptor-related protein 5/6; PP2A, protein phosphatase 2A.
Lithium salts are used to treat bipolar disorder, a mental disease characterized by alternating periods of elation and depression. It is believed that lithium salts are GSK3 inhibitors (IC50 = 2.0 mM) that directly bind to the protein in competition with magnesium ions.(175) Lithium carbonate was assessed in two clinical trials (NCT00790582 and NCT00818389) including ALS patients, and one revealed improved benefits, whereas the other did not find any evidence of clinical benefits.
Tideglusib (112, NP-12, or NP031112; Figure 33), developed by the Zeltia Group in Spain, has a thiadiazolidinone core. This drug is a selective, irreversible, and non-ATP-competitive GSK3β inhibitor with an IC50 value of 251 nM against GSK3β.(176) The experimental results did not suggest that tideglusib forms a covalent bond with Cys199 of GSK3β. However, the irreversible inhibition and the very low turnover rate of GSK3β are principally relevant from a pharmacological perspective of tideglusib and could have substantial implications in the therapeutic potential of GSK3β inhibitors. Tideglusib demonstrated potent anti-inflammatory and neuroprotective effects both in vitro and in vivo.(177) Tideglusib has completed a phase 2 clinical trial for AD. The results revealed that except for some moderate, asymptomatic, fully reversible increases in liver enzymes, this drug was well tolerated.(178) Unfortunately, the drug was withdrawn from AD treatment in 2012. Tideglusib completed phase 2 clinical trials for autism spectrum disorders in 2018. Currently, this drug is in clinical trials for progressive supranuclear palsy (phase 2b)(179,180) and myotonic muscular dystrophy (phase 2), and patients are beginning to be recruited for a congenital myotonic dystrophy trial, a group of genetic disorders that impair muscle functions over a long period of time. Interestingly, tideglusib provides a simple, rapid, and natural tooth repair process, which could provide a potential new approach to clinical tooth restoration.(181)
Figure 33
Figure 33. Chemical structures of GSK3 inhibitors in clinical trials.
LY2090314 (113), developed by Eli Lilly and Company, is a potent competitive GSK3 inhibitor (IC50 values of 1.5 and 0.9 nM against GSK3α and GSK3β, respectively) with limited activity against many other kinases (for example, IC50 = 79 nM against CDK5). This drug has been in clinical trials to study its ability to treat leukemia, advanced cancer, and pancreatic cancer.(182) LY2090314 contains a maleimide core, and many maleimide derivatives, including natural products, have been developed as GSK3 inhibitors.
Recently, many GSK3 inhibitors with different scaffolds have been reported. Figure 34 shows some examples. Among them, compounds 114 (GSK3, IC50 = 8 nM)(183) and CHIR-911 (115, GSK3, IC50 = 5 nM)(184) demonstrated efficacy in treatment of type 2 diabetes, and SB-216763 (116, GSK3α, IC50 = 34 nM), 117 (GSK3β/α, IC50 = 5.9/2.0 nM),(185) SAR502250 (118, GSK3, IC50 = 12 nM),(186) and PF-04802367 (119, GSK3α/β, IC50 = 10/9.0 nM)(187) were reported to have activity in lowering pTau levels in triple-transgenic AD mouse models. Compound 120 is a selective ATP-competitive GSK3β inhibitor (GSK3α/β, IC50 = 40/18 nM). In a mouse model of mania, this compound showed promising efficacy, plasma PK profile, and brain exposure, suggesting that this type of inhibitor has encouraging potential to treat mood disorders.(188) Compound 121 is a GSK3β allosteric inhibitor with an IC50 value of 2.01 nM that demonstrated promise for congenital myotonic dystrophy type 1 and spinal muscular atrophy.(189) Because of rare tridentate interactions with the GSK3 hinge region, BRD1652 (122), having a novel pyrazolo-tetrahydroquinolinone scaffold, inhibits GSK3 very potently (GSK3α/β, IC50 = 0.4/4.0 nM) and with exquisite kinome-wide selectivity. Figure 35 demonstrates the binding mode of BRD3937, an analogue of BRD1652, to human GSK3β.(190) In a dopaminergic signaling paradigm modeling mood-related disorder, this compound displayed effectiveness in vivo.
Figure 34
Figure 34. Chemical structures of several recently reported GSK3 inhibitors.
Figure 35
Figure 35. Binding mode of BRD3937 to human GSK3β (PDB 5HLP). BRD3937 forms three hydrogen bonds with residues Asp133 and Val135.
Inhibitors of GSK3 in other species, such as Plasmodium falciparum GSK3 (PfGSK3), may also have potential uses in medicine (see section 3.17). In addition, selective Trypanosoma brucei GSK3 inhibitors might be suitable as antimicrobial agents against infection by other parasites (see section 3.19).
3.8. p38α Mitogen-Activated Protein Kinase
Excessive production of TNF-α and IL-1β is thought to underlie a few inflammatory disorders. Inhibition of TNF-α function by biological agents such as TNF-α antibodies is effective in the treatment of RA and other autoimmune diseases.
p38 mitogen-activated protein kinases (p38 MAPKs) have four members, p38α, p38β, p38γ, and p38δ. p38α MAPK plays a critical role in regulating the biosynthesis of a number of inflammatory cytokines, such as TNF-α and IL-1β; thus, p38α MAPK inhibitors have been considered to be a promising solution for treatment of inflammatory diseases.(191) Indeed, preclinical studies showed that inhibition of p38α MAPK can effectively inhibit TNF-α production both in vitro and in vivo. In addition, by affecting the formation of reactive oxygen species, p38α MAPK undermines the bioavailability of nitric oxide, leading to endothelial dysfunction and vasoconstriction. Therefore, for the past two decades, the identification and development of small-molecule p38α MAPK inhibitors as orally active therapeutic agents for treatment of inflammatory diseases and cardiovascular diseases have received much interest. Many p38α MAPK inhibitors have advanced into clinical trial studies mainly for treatment of inflammatory diseases. Their structures and clinical information are listed in Table 6. Most of them are for RA; however, little success has been achieved in this field, and interest has turned to their use in other indications, such as COPD.
Table 6. Small-Molecule p38α MAPK Inhibitors Evaluated in Clinical Trials for Treatment of Nononcologic Diseasesa
a
Abbreviations used in this table: AD, Alzheimer’s disease; AS, ankylosing spondylitis; CD, Crohn’s disease; COPD, chronic obstructive pulmonary disease; RA, rheumatoid arthritis.
Although p38α MAPK was thought to be a perfect target for developing anti-inflammatory drugs, more than a dozen chemically different p38α MAPK inhibitors have not yet succeeded after long-term development. In fact, the clinical results are truly disappointing. Many of these inhibitors were found to have significant systemic side effects to various degrees, including hepatotoxicity, cardiac toxicity, and CNS disorders, which may be because p38α MAPK participates in regulation of more than 60 substrates. Additionally, within weeks, tolerance to the anti-inflammatory effect occurred. Others failed owing to unmet endpoints because of a lack of long-term efficacy. For example, in January 2016, due to an unmet primary endpoint in a phase 3a clinical trial and insufficient support for investment in phase 3b of the study, further investigation of losmapimod (124) for acute coronary syndrome was terminated. Thus, to develop feasible anti-inflammatory drugs, evaluating the potential to target upstream MAPKs, such as ASK1 (see section 3.4), is an alternative approach. Another alternative approach is to target the downstream targets of the signaling pathway, such as p38/MAPK-activated kinase 2 (MK2, see section 3.9).
The prodrug strategy has been employed for the development of p38α MAPK inhibitors. BMS-582924 (132) selectively inhibits p38α MAPK with an IC50 value of 13 nM.(192) This compound reduced TNF-α production by 78%. Because of its good pharmacokinetic profile and effectiveness in both a pseudoestablished rat AA model and an acute murine inflammation model, BMS-582924 was advanced into and finished phase 2 clinical trials to study its ability to treat RA and psoriasis-related vascular diseases. To overcome the issues of pH-dependent solubility and exposure related to this compound, BMS-751324 (139, Figure 36A) was developed, which is the clinical prodrug of BMS-582924.(193) BMS-751324 is stable and more soluble than BMS-582924 under both acidic and neutral conditions. Both of these compounds exhibited similar efficacy in a rat adjuvant arthritis model and a rat LPS-induced TNF-α model. BMS-751324 did not show pH-dependent exposure as BMS-582924 did when administered with famotidine in rats and humans. The authors claimed that this prodrug has advanced into clinical trials, but no information could be found at www.clinicaltrials.gov.
Figure 36
Figure 36. (A) Chemical structures of BMS-751324 and MW150. (B) Binding mode of MW150 to human p38α MAPK (PDB 4R3C). MW150 forms hydrophobic interactions with surrounding residues; three hydrogen bonds between MW150 and the Lys53, Met109, and Ser154 residues can be observed.
Recently, a p38α MAPK inhibitor, MW01-18-150SRM (MW150, 140), was advanced into early clinical trials for CNS disorders.(194) MW150 is a highly selective brain penetrant with appropriate pharmacodynamics and is efficacious in diverse animal models of neurologic disorders. Figure 36B shows the binding mode of MW150 to human p38α MAPK.
3.9. p38/MAPK-Activated Kinase 2
p38αMAPK inhibitors have caused significant unwanted side effects in clinical trials, which has prompted researchers to focus their attention on other downstream targets of the signaling pathway, such as p38/MAPK-activated kinase 2 (MK2). MK2 is a member of the serine–threonine kinase family and was the first identified substrate of p38 MAPK. By increasing the stability and translation of the corresponding mRNA, this kinase participates in TNF-α, IL-1β, and IL-6 synthesis and release. Under different inflammatory conditions, MK2 is activated directly by inflammatory signals and stress via p38 MAPK phosphorylation.(195) Mice with p38α MAPK knockout are afflicted with compromised fertility and embryonic lethality, whereas MK2-null mice are not influenced. Furthermore, MK2 knockout mice demonstrated considerably reduced cytokine levels in the serum and brain, along with fewer or no symptoms in lung sensitization or arthritis models. Moreover, after MK2 is depleted, neuroprotective effects are found, suggesting that chronic neuroinflammation related to neurodegenerative diseases, such as PD, AD, and MS, could in part be modulated by MK2 activity. MK2 inhibition has been demonstrated to markedly reduce the production and release of cytokines. In addition, MK2 inhibition may result in effectiveness that is similar or improved compared with p38α MAPK inhibition while avoiding the systemic toxicity exhibited by p38α MAPK inhibitors.(196) Therefore, MK2 inhibition is considered a possible alternative to p38α MAPK inhibition to treat inflammatory diseases, including RA, IBD, IPF, and asthma.(197,198) In addition, MK2 is implicated in the process of tumorigenesis; therefore, MK2 inhibitors may have potential for treatment of nonsmall cell lung cancer (NSCLC).
The crystal structure of MK2 demonstrates that the ATP-binding site is deep and narrow (Figure 37A), which allows only small planar molecules to bind. The catalytic domain of MK2 is highly homologous to that of other kinases, including MK isoforms, hampering the discovery of highly selective MK2 inhibitors. A plethora of MK2 inhibitors have been disclosed, and most are type I (ATP-competitive) inhibitors. However, no MK2 inhibitors have progressed into clinical trials because of their poor physicochemical properties, leading to insufficient oral bioavailability and permeability and mediocre cellular potency and/or efficacy in animal models.
Figure 37
Figure 37. (A) The deep and narrow ATP-binding site of MK2 (PDB 1NY3). An ADP (green ball and stick mode) is shown. (B) Binding mode of an analogue of compound 144 to MK2 (PDB 3FYJ). Two hydrogen bonds can be observed between this compound and Lys93 and Leu141. An atypical CH···O═C hydrogen bond can be found between this compound and Glu139. Additionally, this compound has extensive hydrophobic interactions with Leu70, Val78, Ala91, Lys93, Val118, Met138, Leu141, and Leu193.
Compound 141 (Figure 38), from Boehringer Ingelheim, is a potent MK2 inhibitor (IC50 = 2 nM). PF-3644022 (142, IC50 = 2 nM against MK2) demonstrated oral anti-inflammatory efficiency against both chronic and acute inflammation models in rats.(199) As an anti-TNF-α agent, compound 143 (IC50 = 54 nM against MK2) showed good in vitro cellular effectiveness, as well as in vivo efficacy in a mouse endotoxin shock mode.(200) Compound 144 inhibits MK2 with an IC50 value less than 3 nM.(201) This MK2 inhibitor was obtained by fluorinating a potent ATP-competitive MK2 inhibitor that suffered from insufficient oral bioavailability and permeability disclosed early. Compound 144 displayed improved permeability and other ADME properties, including in vivo clearance and solubility. Figure 37B shows the binding mode of an analogue of compound 144 to MK2.
Figure 38
Figure 38. Chemical structures of MK2 inhibitors discussed in the text.
Because of the high cellular concentration of ATP in cells (approximately 2–5 mM) and the high binding affinity of ATP to MK2 (IC50 = 2 μM), ATP-competitive MK2 inhibitors generally show poor biochemical efficiency. To overcome this and improve selectivity, non-ATP-competitive and uncompetitive MK2 inhibitors have been developed. Among them, compound 145 has an IC50 value of 9 nM against MK2 and an EC50 value of 0.31 μM against human TNF-α.(202) The tetracyclic compound 146 inhibits MK2 with an IC50 value of 2.9 nM and exhibited an EC50 value of 0.26 μM (inhibition of HSP27 phosphorylation in LPS-stimulated THP-1 cells).(203)
3.10. Tropomyosin Receptor Kinases
Tropomyosin receptor kinases (TRKs), belonging to the family of tyrosine kinases, include three members, TRK-A, TRK-B, and TRK-C. TRKs regulate synaptic strength and plasticity in the mammalian nervous system;(204) they are associated with neuronal survival and differentiation through several signaling pathways. Neurotrophins, a family of growth factors, are common ligands of TRKs, and their signaling plays an important role in the nervous system by regulating proliferation, cell survival, the fate of neural precursors, axon and dendrite growth and patterning. In addition, neurotrophin signaling affects the expression and activity of certain proteins, such as ion channels and neurotransmitter receptors (Figure 39). Therefore, interest in developing small-molecule TRK inhibitors, including pan-TRK and selective TRK inhibitors, to modulate neurotrophin activity is increasing. The TRK family has been considered to be a potential target class for treatment of pain.(205) In the field of oncology, TRKs are involved in malignant transformation, metastasis, chemotaxis, and survival signaling. Two TRK inhibitors, larotrectinib and entrectinib, were approved in 2018 and 2019 by the U.S. FDA to treat NSCLC and metastatic solid tumors, respectively, and a few TRK inhibitors are in clinical trials for cancer treatment. For safety issues, it is necessary that TRK inhibitors to treat cancer have minimal brain availability.
Figure 39
Figure 39. TRK signaling pathway. Neurotrophins bind to TRK receptors, leading to recruitment of adaptor proteins, including GRB2, GAB1, SHC, SHP2, FRS2, and SOS. Subsequently, Ras, PLC-γ, and PI3K are activated, triggering the MAPK pathway, calcium mobilization, and the PI3K/AKT/mTOR pathway. These signaling pathways regulate gene expression activation, neurite outgrowth, and neuronal survival associated with pain and cancer.
Because of the high conservation of the ATP-binding sites of the three members in this kinase family, the first developed TRK inhibitors have almost no selectivity among them, i.e., they are pan-TRK inhibitors. Among them, PF-06273340 (147, Figure 40) is currently in clinical trials for pain treatment. As a potent, selective pan-TRK inhibitor inhibiting TRK-A, TRK-B, and TRK-C with IC50 values of 6, 4, and 3 nM, respectively, PF-06273340 is efficacious, peripherally restricted, and well tolerated.(206) PF-06273340 binds to the DFG-out form of TRK (see Figure 41A). This drug progressed into phase 1 clinical trials for development as a pain killer. In healthy human subjects, a randomized, single-dose, double-blind, placebo- and active-controlled five-period crossover study was carried out (NCT02260947) on this drug.(207)
Figure 40
Figure 40. Chemical structures of several reported TRK inhibitors.
Figure 41
Figure 41. (A) Binding mode of PF-06273340 (PDB 5JFX) to TRK-A. PF-06273340 forms three hydrogen bonds with the Met592 and Asp668 residues and two bridged hydrogen bonds with the Arg574 and Glu590 residues. (B) Binding mode of compound 152 (PDB 6D20) in an allosteric pocket of TRK-A. Compound 152 forms four hydrogen bonds with Leu486, Asp668, and Arg673. An NH+–π interaction can be observed. For comparison, PF-06273340 is shown as a green wire model.
CE-245677 (148), identified as an oral pan-TRK/Tie2 inhibitor by Pfizer, has been treated as a potential treatment for certain cancer types; however, identified CNS side effects led to termination of phase 1 multiple-dose trials.(208) This compound demonstrated both efficacy in multiple pain models and CNS side effects. Compound 149 inhibits TRK-A, TRK-B, and TRK-C with IC50 values of 8.4, 6.2, and 2.2 nM, respectively, and exhibits outstanding TRK selectivity against 44 kinases.(209) Compound 149 was predicted to exhibit low metabolic clearance in humans, hence avoiding the potential clearance prediction liability related to PF-06273340. Compound 149, along with two analogues, was regarded as an exciting and promising structurally differentiated asset suitable for advancement into a variety of clinical pain studies. Scientists at Merck reported their efforts to develop a series of several small-molecule selective pan-TRK inhibitors from hits obtained by HTS.(210) Compound 150 exhibited excellent cellular potency and an extended residence time on the enzyme and was chosen for investigation in an inflammatory model and a neuropathic pain model. Compound 151 is a pan-TRK inhibitor with excellent selectivity against other kinases and was designed from the aurora A kinase inhibitor tozasertib, a drug in clinical phase 2 trials for cancer treatment.(211) Compound 151 may serve as an advanced hit compound for treatment of acute and chronic pain or other conditions resulting from abnormal TRK-A activity, such as inflammation and cancer.
TRK-A, also named high affinity nerve growth factor receptor, causes cell differentiation and may be involved in specifying sensory neuron subtypes. Nerve growth factor (NGF) binds to TRK-A, and blockade of the TRK-A signaling pathway by the NGF antibody tanezumab has been clinically validated for pain treatment, which provides clinical proof of concept for the benefit of TRK-A pathway inhibition in pain. This result provides researchers with great motivation for the development of small-molecule selective TRK-A inhibitors to treat chronic pain. For this purpose, adequate TRK-A selectivity over TRK-B and TRK-C is desirable. However, there are no residue differences in the ATP-binding sites among TRK-A, TRK-B, and TRK-C, signifying that it is very challenging to develop selective TRK-A inhibitors that bind to this site. Allosteric TRK-A inhibitors may have improved isoform selectivity. Indeed, compound 152 binds TRK-A in an allosteric pocket located behind the ATP-binding site with an IC50 value of 10 nM (Figure 41B) and demonstrated high selectivity over TRK-B/C and the kinome.(212) This compound was efficacious in preclinical pain models and demonstrated good oral absorption combined with extensive peripheral restriction and a clean in vivo toxicity profile.
AR786, whose chemical structure is not disclosed, is a selective TRK-A inhibitor that binds to an allosteric site. AR786 has IC50 values of 0.6 nM and >1000 nM against human TRK-A and TRK-B in cells and has high off-target kinase selectivity. This compound demonstrated good oral exposure in rodents and maintained high peripheral distribution relative to the CNS. In a rodent model of peripheral pain, inhibition of the TRK-A receptor via allosteric modulation was sufficient to demonstrate significant and sustained relief of nociceptive pain. For pan-TRK inhibitors, such as AR470 or AR772 (structures unknown), there were no observed benefits of simultaneously inhibiting the brain-derived neurotrophic factor/TRK-B axis. AR786 was shown to have similar efficacy in monoiodoacetate and medial meniscal transection models of osteoarthritis pain. AR786 reduced the paw withdrawal threshold and weight bearing asymmetry in both models at a dose of 30 mg/kg (PO, BID) in comparison with sham controls. Although it does not affect joint pathology, AR786 attenuates monoiodoacetate-induced synovitis.(213) AR786 was first developed by Array BioPharma Inc., and in 2016 was codeveloped in collaboration with Asahi Kasei Pharma as a selective TRK-A inhibitor for pain and inflammation.
Brain-derived neurotrophic factor, which binds to TRK-B, might be useful as a therapeutic agent for a variety of neurological disorders. Inhibition of TRK-B may lead to an antidepressant effect. Compound 153, a dihydroxyflavone analogue, is a selective TRK-B agonist that has robust TRK-B activation in the hippocampus of the mouse brain, whereas TRK-A is not activated.(214) Chronic oral administration of this compound markedly reduced immobility in two classical antidepressant behavioral animal models (tail suspension test and forced swim test). Compound 153 has the potential to be a candidate for in-depth drug development for treatment of various neurological diseases, such as depression. 7,8-Dihydroxyflavone (compound 154,7,8-DHF), another potent and selective TRK-B agonist mimicking the effect of brain-derived neurotrophic factor, improved motor function and reduced motoneuron loss in SOD1G93A ALS model mice.(215)
3.11. c-Jun-N-Terminal Kinases
As members of the MAPK family, c-Jun-N-terminal kinases (JNKs) regulate the biological processes of apoptosis, immune response, and autophagy when they are activated by various stimulating factors, including growth factors, cytokines, neurotoxins, oxidative stress, and fatty acids. To date, there are three human JNK genes, jnk1, jnk2 and jnk3, which encode 10 diverse splice JNK variants (four JNK1/2 isoforms and two JNK3 isoforms). JNK1/2 are widely expressed; nevertheless, JNK3 is explicitly expressed in the brain at high levels and in the heart and testis at low levels.(216)
JNK1/2 has been shown to have an important role in autoimmune disorders, such as RA, IBD, endometriosis, and psoriasis. Studies have shown that the release of proinflammatory cytokines, such as TNF-α and IL-1β, is triggered by the JNK pathway.(217) Inhibition of JNKs decreased LPS-induced TNF-α release, reduced immune cell proliferation in multiple sclerosis, and showed anti-inflammatory effects in collagen-induced arthritis.(218)
Among the JNKs, JNK3 has been considered an attractive therapeutic target for CNS disorders, such as AD and PD. JNK3 promotes formation of the amyloid-β (Aβ) product by phosphorylating the Aβ precursor protein.(219) Furthermore, JNK3 is expressed in the Tau protein, affecting the stability of the cytoskeleton.(220) JNK3 also directly phosphorylates Tau protein, regulating the formation of neurofibrillary tangles, which is positively correlated with cognitive impairment and neuron loss. Knockout or inhibition of JNK3 in mice led to amelioration of neurodegeneration in animal models. In addition to the inflammatory and CNS diseases discussed above, JNKs have been considered potential drug targets for cancer, metabolic disorders, fibrosis, and cardiovascular diseases due to their potential pathological functions in vivo.
SP600125 (155, Figure 42) is the first reported potent pan-JNK inhibitor (JNK1, IC50 = 40 nM; JNK2, IC50 = 40 nM; JNK3, IC50 = 90 nM) with poor selectivity over other MAPKs, such as p38 MAPKs and extracellular signal-regulated kinases. SP600125 was used for treatment of various conditions with the aim of exploring the specific roles of JNKs in different diseases. Studies have indicated that SP600125 leads to decreased formation of neurofibrillary tangles and senile plaques and improves AD-associated cognitive deficits in homozygous APPswe/PS 1dE9 double-transgenic mice.(221) In addition, SP600125 showed efficacy in a number of animal models of fibrosis.(222)
Figure 42
Figure 42. Chemical structures of representative JNK inhibitors for treatment of nononcologic diseases.
AS-602801 (156) is another pan-JNK inhibitor (JNK1, IC50 = 80 nM; JNK2, IC50 = 90 nM; JNK3, IC50 = 230 nM) that was identified in the process of drug development for neurological diseases. In 2012, this compound reached phase 2 clinical trial studies to evaluate its ability to treat inflammatory endometriosis,(223) a disorder associated with the presence of endometrial tissue outside the uterine cavity, sensory nerve recruitment, inflammation, and T-cell involvement.
Tanzisertib (157, CC-930), a potent pan-JNK inhibitor (JNK1, IC50 = 61 nM; JNK2, IC50 = 7 nM; JNK3 IC50 = 6 nM) developed by Celgene, was investigated for treatment of discoid lupus erythematosus and IPF in clinical trials in 2011. However, the investigation was discontinued in phase 2 clinical trials for undisclosed reasons.(224)
XG-102, a bidentate peptide JNK inhibitor, targets the JNK-interacting protein binding site to block the interaction of JNK with certain substrates, such as ATF2, c-Jun, and ELK1. It was found that XG-102 potently blocks p38α MAPK signaling and exhibits a synergistic effect with JNK pathway inhibition.(225) A phase 3 clinical trial was completed in patients with acute sensorineural hearing loss in 2016, and phase 3 trials for treatment of postcataract surgery intraocular inflammation were started in 2015. Its derivative XG-104 (JNK1, IC50 = 722 nM; JNK2, IC50 = 155 nM; JNK3, IC50 = 1102 nM) entered phase 2 for dry eye syndrome treatment in 2014.
In addition to pan-JNK inhibitors, development of selective JNK3 inhibitors for CNS treatment has received broad interest in recent years. Compound 158 is a selective JNK3 inhibitor with an IC50 value of 40 nM against JNK3 and showed 2500-fold selectivity over JNK1α1 and JNK2α2 isoforms and excellent kinome selectivity over 398 kinases.(226)In vivo studies showed that compound 158 significantly reduced spatial memory impairment by lowering Aβ accumulation and Tau phosphorylation. Additionally, it exhibited neuroprotective activity in vitro. Compound 159 is a novel selective JNK3 inhibitor with an IC50 value of less than 1 nM against JNK3, 200-fold selectivity over JNK2, 500-fold selectivity over JNK1, and 20 000-fold selectivity over p38α MAPK.(227) However, this compound and its analogues showed poor pharmacokinetic properties in oral dosing; thus, future optimization will require improvement of oral pharmacokinetic properties if oral administration is preferred.
3.12. Leucine-Rich Repeat Kinase 2
As a member of the ROCO protein family, leucine-rich repeat kinase 2 (LRRK2, also known as RIPK7) is a very large multidomain serine–threonine kinase that includes a kinase domain and a GTPase domain.(228) It is comprised of 2527 amino acids and is expressed in many tissues, especially throughout the brain, including the striatum, olfactory bulb, hippocampus, cortex, brainstem, midbrain, and cerebellum. LRRK2 participates in many biological pathways. Mutations in LRRK2, such as G2019S, are related to an increased risk of PD; therefore, LRRK2 is genetically linked to PD.(229) It has been hypothesized that LRRK2 inhibition may be a potential way to alter PD pathogenesis. In addition, LRRK2 is associated with CD, leprosy, and some cancer types; therefore, this kinase target has received great interest for the development of potent brain penetrant inhibitors, and many LRRK2 inhibitors have been reported.(230,231) Potent and selective LRRK2 inhibitors may function as key tools to understand LRRK2 mechanisms and may offer additional insights into the roles of LRRK2 in PD pathogenesis.
The design of LRRK2 inhibitors has been hindered in part by the complexity of this large multidomain kinase, which has not yet been crystallized. However, different potent, brain permeable, selective LRRK2 inhibitors have recently been reported. Figure 43 shows a few well-known LRRK2 inhibitors, including GSK2578215A (160),(232) GNE-7915 (161), GNE-0877 (162),(233) PF-06447475 (163),(234) and compounds 164(235) and 165.(236) Nevertheless, a few preclinical studies have demonstrated that LRRK2 inhibition may lead to potential side effects in peripheral tissues, such as the lung and kidney. However, studies of two LRRK2 inhibitors (GNE-7915 and GNE-0877) confirmed the potential problems induced by inhibition of LRRK2.(237) These assessments of toxicity in rodents demonstrated that these two LRRK2 inhibitors do not cause lung or kidney changes. In primates, normal kidney function was found, but some toxicity issues did exist in the lungs. In two mouse models of LRRK2-associated PD, GNE-7915 enhanced dopamine release and improved cell function; thus, it was concluded that GNE-7915 should be effective for treatment of PD.(238)
Figure 43
Figure 43. Chemical structures of representative selective LRRK2 inhibitors.
To date, two LRRK2 inhibitors, DNL-201 (likely to be GNE-7915) and DNL-151 from Denali Therapeutics, have been in phase 1 clinical trials for PD treatment. In healthy volunteers, the phase 1a study of these two drugs showed good tolerability and inhibition of peripheral LRRK2 kinase activity. After completing their phase 1 clinical trials, Denali Therapeutics decided to initiate testing of one of the two LRRK2 inhibitors in a phase 1b study, enrolling patients with LRRK2-associated PD to further evaluate safety as well as biomarkers.
3.13. Ketohexokinase
In recent decades, the utilization of fructose, or fruit sugar, as a common food additive and sweetener has increased and has been associated with metabolic disorders, including nonalcoholic fatty liver disease, steatohepatitis, insulin resistance, and cardiovascular disease. Ketohexokinase (KHK, also known as hepatic fructokinase) catalyzes the phosphorylation of fructose to produce fructose-1-phosphate, which initiates the metabolic cascade of fructose.(239) KHK has two isoforms, KHK-A and KHK-C. The latter is the primary enzyme for fructose metabolism because it has a lower KM and a higher Vmax than KHK-A. Fructose is primarily metabolized in turn by the intestines, liver, pancreas and kidney, all of which express KHK-C. Therefore, KHK has been regarded as a promising therapeutic target for the development of medical agents to treat nonalcoholic fatty liver disease. hyperlipidemia, insulin resistance, and obesity.
A few KHK inhibitors have been reported. Compound 166 (Figure 44), a KHK inhibitor with an IC50 value of 330 nM, was identified through a fragment-based drug design paradigm.(240) Compound 167 was identified as a KHK inhibitor (IC50 values of 0.45 and 0.39 μM against hKHK-C and hKHK-A, respectively) with minimal off-target activity through a combination of structure-based drug design, fragment-based screening, and parallel medicinal chemistry.(241) This compound has several positive attributes of a lead. In vivo pharmacology studies showed that 167 induced a dose-dependent decrease in fructose-1-phosphate formation in the liver and kidney with concomitant increases in plasma fructose concentrations. PF-06835919 (168), built upon compound 167, is a highly potent KHK inhibitor (IC50 value of 10 nM) with a core of 3-azabicyclo[3.1.0]hexane acetic acid. It is interesting to note that after modification of the (S)-3-methylpyrrolidin-3-ol moiety of compound 167, the obtained KHK inhibitors, for example, PF-06835919, may have a different rotated binding mode, as demonstrated in Figure 45. In this binding mode, the carboxylate group of PF-06835919 has three hydrogen bonding interactions with the cationic guanidinium group of Arg108 and the backbone NHs of Ala256 and Gly257; another hydrogen bond bridged by a bound water molecule between the pyrimidine ring and the carbonyl group of Cys282 can be observed; and the trifluoromethyl group fills the hydrophobic pocket defined by the Ala244, Pro246, and Pro247 residues.
Figure 44
Figure 44. Chemical structures of three reported KHK inhibitors.
Figure 45
Figure 45. Binding mode of PF-06835919 to KHK (PDB 6W0Z). Three hydrogen bonds with Arg108, Ala256, and Gly257 and a bridged hydrogen bond with Cys282 can be observed between PF-06835919 and KHK.
The in vivo pharmacokinetic properties of PF-06835919 were determined in rats and dogs, and in both species, this KHK inhibitor demonstrated a moderate to long elimination half-life, negligible renal excretion as an unchanged parent and high oral bioavailability. The observed dose-dependent decrease in hepatic and kidney fructose-1-phosphate indicates inhibition of liver and kidney KHK. Representing a first-in-class small-molecule KHK inhibitor, PF-06835919 has entered phase 2 clinical trials for treatment of nonalcoholic fatty liver disease and steatohepatitis.
3.14. G Protein-Coupled Receptor Kinase 2
Belonging to the AGC family, G protein-coupled receptor kinases (GRKs) canphosphorylate activated G protein-coupled receptors and thereby initiate their uncoupling from heterotrimeric G proteins and their internalization. GRKs have seven isoforms and are divided into three subfamilies: GRK1 (including GRK1 and 7), GRK2 (including GRK2 and 3), and GRK4 (including GRK4–6). GRK2, also named β-adrenergic receptor kinase 1 (βAR-kinase 1), phosphorylates agonist-occupied βAR and promotes arrestin-mediated binding of βAR to the Gβγ subunit of the G-protein and βAR-G protein uncoupling, further leading to βAR desensitization and downregulation (Figure 46).(242) Increased βAR desensitization and downregulation are correlated with chronic heart failure, which may lead to death. In addition, upregulation of GRK2 influences cardiac glucose uptake, leading to abnormal cardiac metabolism and affecting new cardiomyocyte growth.(243) Studies have shown that GRK2 inhibition by overexpressed βARKct, a peptide GRK2 inhibitor from a portion of the c-terminus of GRK2, or cardiac-specific GRK2 gene ablation leads to increases in βAR density and βAR responses and improved cardiac function and survival in several heart failure models.(244,245)
Figure 46
Figure 46. GRK2 signaling pathway. In the adrenal medulla and cardiac sympathetic nerve terminal, upregulation of GRK2 leads to α2 adrenergic receptor (α2AR) dysfunction, causing a massive release of catecholamines (norepinephrine and epinephrine). Catecholamines in turn stimulate the βARs present on cardiomyocytes, activating AKT and GRK2. GRK2 blocks sphingosine 1-phosphate (S1P) receptor 1 (S1PR1) signaling, which is involved in regulation of the contractile response and cardiac hypertrophy. In addition, GRK2 phosphorylates insulin receptor substrate-1 (IRS1), blocking glucose transporter type 4 (GLUT4) translocation from the cytosol to the plasma membrane. GRK2 also regulates β-oxidation rates and increases activation of the mitochondrial permeability transition pore (MPTP), which is associated with cellular death.
Paroxetine (169, Figure 47), a serotonin reuptake inhibitor, has been approved by the FDA. It has been used for treatment of depression, anxiety, obsessive–compulsive disorder, and posttraumatic stress disorders. It also has modest potency against GRK2, with an IC50 value of 1.1 μM (at 5 μM ATP) and >6-fold selectivity for GRK2 over other GRKs. Paroxetine was shown to improve left ventricular activity and decrease cardiac remodeling in a mouse model of myocardial infarction by inhibiting GRK2.(246) Optimized from paroxetine, GSK180736A (170), with an IC50 value of 0.77 μM against GRK2, demonstrated >100-fold selectivity against other GRKs. However, it lacks selectivity over ROCK1 and shows poor bioavailability.(247)
Figure 47
Figure 47. Chemical structures of representative GRK2 inhibitors discussed in the text.
The natural product balanol (171) is a pan-GRK inhibitor that inhibits GRK2 with an IC50 value of 50 nM (at 3 μM ATP) but also potently inhibits GRK1 and GRK3–7 (GRK1, IC50 = 340 nM; GRK3, IC50 = 47 nM; GRK4, IC50 = 260 nM; GRK5, IC50 = 160 nM; GRK6, IC50 = 490 nM; and GRK7, IC50 = 180 nM). In addition, it inhibits AGC.(248) As a derivative of balanol, Takeda103A (172), developed by Takeda Pharmaceuticals, displayed improved activity and selectivity, with an IC50 value of 20 nM (at 5 μM ATP) against GRK2 and was 50-fold more potent against GRK2 than against other tested AGC kinases. However, Takeda103A failed to enter clinical trials because of poor pharmacokinetic properties.(249) Combining the pharmacophore of GSK180736A with Takeda103A, CCG-224406 (173) was identified as a GRK2 inhibitor with an IC50 value of 130 nM that showed >700-fold selectivity over other GRK subfamilies and ROCK1. CCG-224406 showed significant cardiomyocyte potency in mouse cardiomyocytes in vitro.(250)
The novel selective GRK2 inhibitor 174 (IC50 = 18 nM) was designed from a hydrazone derivative and a 1,2,4-triazole derivative that were hit compounds identified by HTS.(251) Compound 174 showed good selectivity against GRK1, 5, 6, and 7, protein kinase C (PKC), and ROCK (GRK1, IC50 = 3100 nM; GRK5, IC50 = 2300 nM; GRK6, IC50 > 30000 nM; GRK7, IC50 > 25000 nM; PKC, IC50 = 8100 nM; ROCK, IC50 = 1400 nM) but exhibited almost comparable inhibitory activity against GRK3 (GRK3, IC50 = 5.4 nM). Compound 174 potentiated βAR-mediated cAMP accumulation and arrested internalization of βARs in β2AR-expressing HEK293 cells treated with isoproterenol, suggesting that it could be a potential candidate for heart failure treatment. However, currently, no GRK2 inhibitors are in clinical trials or have been approved.
3.15. NF-κB Inducing Kinase
As a family of transcription factors, NF-κB controls DNA transcription, cytokine generation, and cell survival. NF-κB exists in almost all animal cell types and is involved in cellular responses to stimuli and the immune response to infection. NF-κB signaling occurs through two distinct canonical and noncanonical pathways.(252) NF-κB inducing kinase (NIK, also known as mitogen-activated protein kinase kinase kinase 14, MAP3K14) is a serine/threonine protein kinase. As a critical kinase in the alternative NF-κB activation pathway, NIK binds to TNF receptor-associated factor 2 and stimulates NF-κB activity. It mediates noncanonical NF-κB signaling downstream of multiple TNF family members. Augmented NF-κB activities are related to inflammatory diseases, autoimmune diseases, and cancer and are correlated with abnormal stabilization and activation of NIK. Therefore, NIK has been assumed to be an attractive drug target to develop therapeutic agents for treatment of SLE, inflammatory diseases, and cancer, among others. However, although NIK inhibitors have great potential, only a few NIK inhibitors have been reported, and no NIK inhibitors have advanced into clinical trials.
Compound 175 (Figure 48), containing an alkynol fragment, was developed by Amgen. This compound has excellent NIK inhibitory potency (Ki = 0.4 nM). It was confirmed that 175 protects the liver from oxidative stress, inflammation induced by toxin, and injury.(253) To improve the potency and selectivity of a series of NIK inhibitors with a benzoxepine core over PI3Kδ, structure-based drug design was employed, and the selective and potent NIK inhibitor 176 was obtained. This NIK inhibitor cleanly inhibits the noncanonical over the canonical NF-κB pathway in HeLa cells.(254)
Figure 48
Figure 48. Chemical structures of six NIK inhibitors discussed in the text.
Compound 177 was identified as a highly potent and selective NIK inhibitor (Ki = 0.17 nM) through a structure-guided scaffold-hopping campaign.(255)Figure 49 shows its binding mode to murine NIK (PDB 6G4Z). Two hydrogen bonds are formed between this compound and the hinge region of NIK, and the alkyne motif of compound 177 traverses a narrow channel, allowing access to a small pocket wherein 177 makes two hydrogen bonds and hydrophobic interactions that drive both NIK potency and broad kinome selectivity. SMI1 (178), an analogue of 177, can treat experimental lupus in NZB/W F1 mice and led to improved survival, lower proteinuria scores, and reduced renal pathology, demonstrating that NIK inhibition is a potential strategy for SLE treatment.(256)
Figure 49
Figure 49. Binding mode of compound 177 to murine NIK (PEB 6G4Z). Compound 177 forms hydrophobic interactions with surrounding residues, and four hydrogen bonds between this compound and residues Glu442, Glu472, Leu474, and Asp536 can be observed.
Compound 179, obtained through structure-based drug design, is a highly selective NIK inhibitor (IC50 = 9.87 nM). This compound demonstrated selective inhibitory activity toward LTβR-dependent p52 translocation and NF-κB2-related gene transcription.(257) In an imiquimod-induced psoriasis mouse model, oral administration of different doses of compound 179 showed effective antipsoriasis activity with alleviation of invasive erythema, swelling, skin thickening, and scales. Compound 180 (IC50 = 9.1 nM against NIK) is orally bioavailable in mice and efficiently suppresses the expression of NIK-induced liver inflammation-related genes in isogenic primary hepatocytes, indicating the therapeutic potential of NIK inhibitors for treatment of liver inflammatory diseases.(258)
3.16. Polo-like Kinase 2
The family of Polo-like kinases (PLKs) has five members, PLK1–5. All of them are highly conserved serine–threonine kinases that participate in the mammalian cell cycle and are involved in cell growth and checkpoint regulation of mitosis in various species. Among these five members, PLK1, having pivotal roles in mitosis, has significant clinical relevance and has been considered a bona fide target for the development of anticancer drugs.(259) Several PLK1 inhibitors, including BI 2536, onvansertib, and BI 6727 (volasertib), have entered into clinical trials for cancer treatment and have shown promising anticancer effects.(260) However, whether PLK1 is an oncogene is under debate because data have shown that PLK1 can sometimes act as a tumor suppressor.(261)
Both PLK2 and PLK3 are acidophilic kinases; however, our present knowledge of their biological roles is limited and fragmentary.(262) PLK2 and PLK3 are highly homologous to PLK1 and have been documented as tumor suppressor genes, but recent studies have shown that PLK2 is an independent prognostic marker and regulates tumor growth and apoptosis via the Fbxw7/cyclin E pathway in colorectal cancer and that PLK2 acts as a promoter in human tumor cells.(263) PLK2 is expressed in several cancer cell lines, and selective PLK2 inhibitors exhibit antitumor activity in the nanomolar range against different cancer cell lines.(264)
α-Synuclein is the major component of Lewy bodies, and PLK2 phosphorylates α-synuclein at serine 129, suggesting that PLK2 may play a key role in the progression of Parkinson’s-like pathologies.(265) PLK2 regulates α-synuclein levels through a transcription-based mechanism, which is active in cells and brain tissue. Inhibition of PLK2 may provide an alternative strategy for modulating α-synuclein levels and thereby for altering disease progression in synucleinopathies.(265) Therefore, PLK2 may serve as a potential therapeutic target for PD and related Lewy body diseases. To examine this hypothesis, Elan Pharmaceuticals designed and synthesized selective PLK2 inhibitors with potency in the nanomolar range.(266) These PLK2 inhibitors, such as ELN 582175 (181), ELN 582646 (182), and compound 183 (Figure 50), are highly selective, orally active, and brain permeable. ELN 582175 significantly reduced the level of phosphorylated α-synuclein in the rat brain after oral administration and has been considered a useful probe for future studies of PD.(267)
Figure 50
Figure 50. Chemical structures of a few reported selective PLK2 inhibitors.
Our group also developed selective PLK2 inhibitors (for example, compounds 184 and 185) using the selective PLK1 inhibitor BI 2536 as the starting point.(264) BI 2536, an ATP-competitive inhibitor, is a dihydropteridinone derivative exhibiting nanomolar potency against PLK1.(268) This compound exhibited significant anticancer activity and was well tolerated in the first clinical trials in patients with refractory or relapsed AML and advanced solid tumors. However, further development of BI 2536 was terminated by Boehringer Ingelheim.
3.17. Plasmodial Kinases
The emergence of resistance to current antimalarial drugs, including artemisinin, demands novel therapeutic strategies to treat malaria. Five Plasmodium species cause human malaria. Among them, Plasmodium falciparum (P. falciparum) is the most virulent species of human malaria and was responsible for 50% of all malaria cases and 91% of the 446 000 malaria-related deaths worldwide in 2016. P. falciparum provides many protein kinases and a small set of lipid kinases involved in critical signaling pathways at different stages of the parasite life cycle to develop next-generation antimalarials. Plasmodial kinases offer a possible advantage in that high selectivity over human kinases can be achieved.(269) This section summarizes several plasmodial kinases that have been targeted to develop antiplasmodial agents, and many potent inhibitors of these kinases have been reported. Currently, among the many disclosed inhibitors targeting plasmodial kinases, MMV048 (186, previously MMV390048, Figure 51), a P. falciparum phosphatidylinositol 4-kinase (PfPI4K) inhibitor, has progressed to human clinical trials to treat malaria.
Figure 51
Figure 51. Chemical structures of inhibitors of plasmodial kinases discussed in the text.
3.17.1. PfPI3K and PfPI4K
PfPI3K and PfPI4K, two lipid kinases, are essential survival phosphoinositide lipid kinases (PIKs) of the parasite and are considered promising targets to treat malaria.(270) To date, the discovery of PfPI3K inhibitors is still in its infancy, and very few PfPI3K inhibitors have been reported. However, a well-known antimalarial, dihydroartemisinin (187), was shown to inhibit PfPI3K with an IC50 value of 4.1 nM.(271)
PfPI4K, operating in all life-cycle stages of the parasite, is a novel drug target for the development of next-generation antimalarial drugs to cure, prevent, and block transmission of the disease. Many PfPI4K inhibitors have been reported.(270) Among them, MMV048 (186), with a core of 2-aminopyridine, demonstrated high antiplasmodial activity against K1 (chloroquine and drug-resistant strain, IC50 = 0.025 μM) and NF54 (chloroquine-susceptible strain, IC50 = 0.028 μM) and was superior to chloroquine against the K1 strain. This compound can block all life cycle stages of the malaria parasite and has favorable ADMET and PK properties.(272) MMV048 completely cured P. berghei-infected mice with a single oral dose of 30 mg/kg. At present, this drug is in phase 2a in Ethiopia for malaria treatment.
A cell-based screen against P. falciparum asexual blood-stage parasites identified a new class of antimalarials with an imidazopyrazine scaffold (see the typical compound KAI715, compound 188).(270) Such compounds are active against several drug-resistant strains, with IC50 values of 27–70 nM. In rodent malaria models, they displayed potent therapeutic, preventive, and transmission-blocking activities. These compounds were active against blood-stage field isolates of the major human pathogens P. falciparum and Plasmodium vivax and inhibited liver-stage hypnozoites in the simian parasite Plasmodium cynomolgi. Forward genetics was used to elucidate their targets, and the experimental data, including convincing chemical and genetic evidence, confirmed that PI4K is the direct target.
3.17.2. PfGSK3
PfGSK3 was demonstrated to be an important enzyme for completion of the asexual erythrocytic cycle of the parasite and consequently was suggested as a putative antimalarial drug target.(273) Compound 189 inhibits PfGSK3 with an IC50 value of 0.48 μM and is selective over the mammalian GSK3 orthologue.(274)
3.17.3. P. falciparum Cyclin-Dependent-like Kinase (PfCLK3)
PfCLK3, which is involved in multiple parasite life stages, has recently been validated as an effective target.(275)PfCLK3 is the key regulator of RNA processing and maintains the asexual blood stage of both P. falciparum and P. berghei. Inhibition of PfCLK3 by SMKIs would be an effective strategy to kill the parasite at all stages of the life cycle, including the blood, liver, and sexual stages, in which RNA splicing is required. A probe molecule, TCMDC-135051 (190), was identified as a PfCLK3 inhibitor that kills blood-stage P. falciparum. This compound has parasiticidal activity and led to a decrease in more than 400 gene transcripts essential for parasite survival by inhibiting PfCLK3. Because of the homology between CLK3 orthologues in other Plasmodium species, TCMDC-135051 showed potent inhibitory activity against CLK3 from P. vivax and P. berghei and killed the blood stages of P. berghei and Plasmodium knowlesi. In addition, PfCLK3 inhibition kills liver-stage P. berghei parasites and prevents P. berghei infection in mice; furthermore, by blocking infection of mosquitoes, this kinase prevents the development of P. falciparum gametocytes. TCMDC-135051 showed selectivity for PfCLK3 compared with the closely related human kinase CLK2, the human orthologues of PfCLK3, and PfCLK1 and other parasite kinases.
3.17.4. P. falciparum Calcium-Dependent Protein Kinases (PfCDPKs)
In Plasmodia, CDPKs are the main calcium signaling transducers. PfCDPK1, which is highly expressed in the asexual blood and mosquito stages, is associated with parasite motility, host invasion by P. falciparum, microneme secretion, and gametogenesis and is an interesting target for blocking transmission. Many PfCDPK1 inhibitors have been reported, but most of them lose the connection between enzyme potency and antiplasmodial activity. Compound 191 (IC50 = 12 nM against PfCDPK1) demonstrated significant efficacy in a P. berghei mouse infection model.(276)PfCDPK4 is vital for exflaggelation and sporozoite invasion of hepatocytes. Although unimportant for blood stage parasite proliferation, inhibitors of PfCDPK4 would be valuable as part of an extended gametocyte transmission blocking regimen. BKI-1 (192) inhibits PfCDPK4 with an IC50 value of 4 nM and blocks exflaggelation in P. falciparum with an EC50 value of 35 nM.(277)
3.17.5. P. falciparum cGMP-Dependent Protein Kinase (PfPKG)
PfPKG targets at least 69 proteins and influences several cellular activities in Plasmodia at various stages of the life cycle. PfPKG is essential for blood stage replication in the human host. Inhibition of PfPKG results in blockade of egress from mature schizonts. Compound 193 inhibits PfPKG very potently (IC50 = 0.16 nM) and selectively, displays significant potency over the asexual blood stage of P. falciparum, and blocks gametocyte transmission to Anopheles mosquitoes.(278)
3.17.6. P. falciparum MO15-Related Kinase (PfMRK)
PfMRK belongs to the CDK family and plays a critical role in DNA replication and transcriptional control. On the basis of the structural differences within the ATP-binding pockets between PfMRK and CDK7 (mammalian homologue of PfMRK), many specific PfMRK inhibitors have been identified. Among them, compound 194, a flavonoid natural product, inhibits PfMRK with an IC50 of 40 nM and demonstrated antiplasmodial activity.(269)
3.18. Toxoplasma gondii Calcium Dependent Protein Kinase 1
As a widespread parasite, Toxoplasma gondii (T. gondii) infects all warm-blooded animals (including humans) and is transmitted through food (undercooked meat or oocyst-contaminated food) and water.(279) Its tachyzoites disseminate to all organs and readily form tissue cysts within endothelial cells in the lung or retina and neurons in the brain. Most T. gondii infections in humans can be well controlled by immune responses, resulting in mild illness. However, because tachyzoites reemerge and proliferate rapidly, immunocompromised patients may suffer from toxoplasmosis, an infectious disease with serious risks, including toxoplasmic encephalitis, pneumonia, and retinitis. In addition, toxoplasmosis can cause much harm to immunocompromised organ transplant and cancer chemotherapy patients.
Currently, inhibition of the folate pathway, for example, with the dihydrofolate reductase blocker pyrimethamine and the folate antagonist sulfadiazine, is being tested for toxoplasmosis treatment in clinical trials. However, these drugs exhibit several side effects, including allergic reactions to the sulfonamide drug and bone marrow suppression due to the pyrimethamine drug. In addition, although effective against acute infection, this therapy is unable to cure chronic infection.
T. gondii calcium-dependent protein kinase 1 (TgCDPK1) is a crucial kinase for the intracellular phases of T. gondii infection, controlling microneme secretion. It has an essential role in parasite motility, cell invasion, and egress. Inhibition of TgCDPK1 has been a potential strategy for toxoplasmosis treatment. Genetic or pharmacological deficiency of TgCDPK1 displayed antiparasitic efficacy in vitro and reduced established T. gondii infection in mice.(280) Moreover, TgCDPK1 possesses a special Gly gatekeeper in its ATP-binding pocket, which is entirely unprecedented in human kinases.(281) This unusual feature indicates that TgCDPK1 could be an effective and safe target for the development of antiparasitic drugs.
A series of pyrazolopyrimidine-containing TgCDPK1 inhibitors derived from ATP were identified.(282,283) To enhance selectivity and potency, a large hydrophobic substituent at the C-3 position of the pyrazolo-pyrimidine scaffold is provided to occupy the hydrophobic pocket formed by the presence of the special small Gly gatekeeper residue. Among these compounds, compounds 195 and 196 (Figure 52) are the most potent representative TgCDPK1 inhibitors, with IC50 values of 3.4 and 0.69 nM, respectively. Compound 197 is a potent TgCDPK1 inhibitor (IC50 = 1 nM) without hERG inhibitory activity that leads to cardiotoxicity risk in humans.(284) To improve the metabolic stability of the methylene linkage at the C-3 position of compound 197, a heteroatom linkage was introduced to replace it, resulting in compound 198 (IC50 = 10.9 nM), which showed good selectivity and significant efficacy in vivo.(285) Compound 199 (IC50 = 16.5 nM) also displayed good activity, selectivity, safety, and efficacy in vivo.(286)
Figure 52
Figure 52. Chemical structures of TgCDPK1 inhibitors discussed in the text.
As a kinase in the same family, calcium/calmodulin-dependent protein kinase II (CaMKII) mediates the binding/entry of Japanese encephalitis virus, dengue virus and Zika virus of Flaviviridae, which are associated with several severe diseases, such as dengue shock syndrome, Guillain–Barré syndrome, and birth defects.(287) It was reported that compound 200 has potent inhibitory activities against CaMKII, with an IC50 value of 0.79 μM and EC50 values of 1.52 and 1.91 μM toward dengue virus and Zika virus infections in human neuronal BE(2)C cells, respectively.(287) Furthermore, in mouse challenge models, compound 200 markedly lowered the viremia level and increased animal survival time.
3.19. Miscellaneous
In this Perspective, we have already illustrated many kinases for which small-molecule medical agents have been successfully applied (with inhibitors already approved) or have potential (with inhibitors reported) for treatment of nononcologic diseases. In addition, many small-molecule inhibitors of many other kinases present in humans or other species have been reported to have biological activities against different nononcologic disease models. Table 7 summarizes such kinases and their representative inhibitors, most of which were gleaned from articles published in the Journal of Medicinal Chemistry from 2010 to present.
Table 7. Reported Miscellaneous SMKIs with the Potential to Treat Nononcologic Diseases(288−353)
a
No determination
b
The activity of ULK1 activator.
4. Perspectives and Conclusion
ARTICLE SECTIONS
Because of the similarities among their ATP-binding pockets and the required inhibitory potency to compete with ATP concentrations, which are in the millimolar range in cells, kinases were recognized as difficult targets for drug discovery many years ago when scientists began to try to identify inhibitors to target them. However, great successes have been achieved in targeting kinases, and more than 60 SMKIs have been marketed worldwide in the past two decades. This is an unparalleled achievement in the history of pharmaceutical research, and kinase inhibitor discovery is currently a burgeoning field and is very inspiring. Most of these SMKIs are for cancer treatment. Although it is assumed that oncology will remain the main focus of kinase drug discovery, an increasing number of disclosed SMKIs can treat diseases other than cancer, as we have discussed in this Perspective. There are great opportunities and challenges in developing SMKIs for nononcologic diseases. One focal challenge is that clinical safety for medicines intended for nonlife-threatening indications that require long-term treatment is much more important than for cancer. Therefore, in the nononcologic therapeutic field, SMKIs with sufficient safety profiles are highly desired for application in the clinic.
4.1. Explore New Kinase Targets
The human kinome along includes 518 kinases. Among the kinases in humans, to date, marketed drugs have been successfully produced to target only approximately 40 kinases, leaving more than 90% of the kinome untapped. The majority of kinomes have been understudied, and our understanding of kinase signaling networks and disease pathologies is limited, demonstrating that the field of SMKI discovery is still immature. Therefore, validation of novel kinase targets is necessary for the discovery of more SMKIs for oncology and nononcology therapeutic areas. To this end, it is necessary to explore new kinases to identify their detailed diverse biological processes and functions. A deep understanding of kinase functions and their dysregulation in human disease might result in the identification of more kinase targets to meet unmet medicinal needs.
For the kinases of other species, no small-molecule inhibitors have been approved. By exploring novel kinases in species other than humans, veterinary medications may be developed. Oclacitinib, a JAK inhibitor controlling pruritus and atopic dermatitis in dogs, is one example. More importantly, in the field of infectious disease, by targeting kinases belonging to parasites, viruses, bacteria, or fungi and developing selective and potent small-molecule inhibitors, it should be feasible to obtain next-generation antimicrobial drugs to kill these microorganisms and protect against them. To avoid possible side effects, the selectivity of the developed SMKIs over mammalian orthologues is very important. It should be noted that targeting kinases of other species is still in its infancy.
4.2. Deeply Understand Already Targeted Kinases
Inhibitors of many kinases have already been approved to treat cancer, and inhibitors of many other kinases have demonstrated promising medical potential for cancer treatment in clinical trials or in preclinical studies. A deeper understanding of the biological functions of these kinases may allow inhibitors to be repurposed and applied to nononcologic diseases.
For example, phosphoinositide-dependent protein kinase 1 (PDK1) has attracted much interest for the development of anticancer agents. Biological studies of PDK1 have indicated that this kinase reduces the activity of TACE-mediated α-secretase and accelerates disease progression in AD and prion-related diseases,(354) which indicates that PDK1 may act as a novel target for AD. However, this genetic validation requires proof of concept to ensure the efficacy and safety of PDK1 inhibitors to treat AD.
Another example is anaplastic lymphoma kinase (ALK). ALK inhibitors, such as crizotinib, have been successfully developed for cancer therapy. ALK is mostly expressed in the brain and is therefore related to cognition and neuronal development. Nevertheless, its functions in the CNS are not clear. To elucidate these functions, scientists at Takeda Pharmaceuticals developed a potent selective and brain penetrant ALK inhibitor by employing a scaffold hopping strategy. This ALK inhibitor can decrease the p-ALK level in the brain and may serve as a valuable tool compound to clarify the mechanism underlying ALK-mediated brain functions and the medical applications of ALK inhibition for CNS disorders, such as cognitive impairment, anxiety, and depression.(290)
4.3. Develop Dual or Multitarget Kinase Inhibitors
The severity and heterogeneity of some types of B-cell malignancies and autoimmune diseases make it necessary to simultaneously target two or more signaling pathways that are disease-relevant; therefore, developing SMKIs that target dual (for example, cerdulatinib) or multiple kinases (for example, nintedanib) represents a feasible strategy to elicit several benefits relative to selective SMKIs. These benefits include (1) control over a wider range of disease etiologies, (2) the possibility of selection so that bypass disease mechanisms can be reduced, and (3) lower-level suppression of specific targets can be sufficient to adjust the activities of certain diseases.(355)
4.4. Develop Highly Selective Kinase Inhibitors
Occasionally, dual or multitarget kinase inhibitors are anticipated; nevertheless, in most cases, to develop drug candidates with satisfactory therapeutic indexes, particularly for nonlife-threatening diseases, SMKIs with good isoform and kinome selectivity are of great interest. Such selective kinase inhibitors can also be employed as pharmacological tools to further investigate the biological roles of kinases or related signaling pathways. In kinase inhibitor discovery, obtaining high selectivity is a long-standing problem.(356) Obtaining targeted kinase selectivity to reduce off-target-mediated side effects or toxicity is particularly important for SMKI development in nononcology therapeutic areas. Unlike cancer, most nononcologic diseases, including inflammatory disorders and autoimmune diseases, are not life-threatening and require a long duration of treatment. These types of diseases require much safer treatment options than cancer. At present, the majority of approved SMKIs and SMKIs in preclinical studies are type I or type II kinase inhibitors that occupy the ATP-binding pockets of kinases. The structural and sequence similarities of ATP-binding pockets make selective inhibition of different kinases a formidable task. For type I (ATP-competitive) or type II SMKIs, taking advantage of subtle differences among the binding sites in a kinase family might be a feasible strategy to design and identify selective kinase inhibitors.(260)
To circumvent this, allosteric inhibitors (type III and type IV) targeting sites different from the orthostatic ATP-binding pockets have been discovered. Compared with ATP-competitive inhibitors, due to the structural differences in their allosteric sites, allosteric inhibitors may have higher selectivity among the kinome, improved physiochemical properties, and better side effects or toxicity profiles. In addition, allosteric inhibitors may have the potential to overcome drug resistance, which is related to the administration of ATP-competitive kinase inhibitors.(357,358) For example, TYK2 has a unique catalytically inactive pseudokinase domain, and BMS-986165, a compound targeting this domain, has very high selectivity against TYK2 in the JAK family. GSK2982772, a type III RIPK1 inhibitor, exhibits excellent kinome selectivity, i.e., monokinase selectivity, which may be because this compound is an allosteric inhibitor.
Types I–IV SMKIs can be covalently or noncovalently bound to their targets. Covalent kinase inhibitors have received significant attention due to their potential for high selectivity, sustained target inhibition, better ligand efficiency, improved pharmacodynamics, ameliorated drug resistance, and high systemic drug exposure. Therefore, developing covalent kinase inhibitors is another feasible way to obtain better medications for both cancer and nononcologic diseases if there is a reactive residue in or in close proximity to the active site. To this point, targeting of BTK has shown great success, and most BTK inhibitors on the market or in clinical trials are covalent.
4.5. Proteolysis Targeting Chimera (PROTAC)
Rather than inhibiting a protein, a PROTAC induces selective intracellular proteolysis and then degrades the protein. A PROTAC consists of two protein-binding molecules that are covalently linked with each other: one binds to a target protein for degradation and the other is capable of engaging an E3 ubiquitin ligase. PROTACs provide major advantages over occupancy-based inhibitors and have received much attention for drug discovery. In the field of kinases, PROTACs are still in the early preclinical stages but have demonstrated promise.(359) In the future, more kinases could be explored so that they can be degraded directly by ubiquitylation.
Drug discovery research on kinases has achieved dramatic progress in the past two decades. In the United States, 10 SMKIs have been approved for treatment of several nononcologic diseases. However, each of these drugs has several unwanted side effects. For better medicines to meet unmet significant medical needs, including cancer, inflammatory diseases, CNS disorders, and cardiovascular diseases, among others, the structural diversity, kinase selectivity, and toxicity profiles of SMKIs still need to be improved. With a much deeper understanding of different kinases and accumulated medicinal chemistry knowledge obtained from developing SMKIs, it is anticipated that, in the near future, more SMKIs with better treatment effects will be approved and enter the market for treatment of both cancer and nononcologic diseases.
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.
The authors declare no competing financial interest.
Author Information
ARTICLE SECTIONS
- Xiaoxiao Yang - Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China;
http://orcid.org/0000-0003-0290-2844
The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.
The authors declare no competing financial interest.
Biographies
ARTICLE SECTIONS
Zhouling Xie
Zhouling Xie received his bachelor’s degree from China Pharmaceutical University, where he also obtained his Ph.D. in Medicinal Chemistry under the supervision of Professor Zhiyu Li. In 2017, he became a member of the Department of Pharmaceutical Sciences and Engineering, Hefei University of Technology in China. He works as a lecturer and medicinal chemist, and his current main research interests focus on the following topics: (i) discovery of selective factor XI inhibitors and (ii) design and study of kinase inhibitors, including PLK inhibitors and CDK inhibitors.
Xiaoxiao Yang
Xiaoxiao Yang received her Ph.D. from Nankai University in 2017 and then worked at Hefei University of Technology as an associate professor. Her research interests include vascular biology, liver diseases, and cancer.
Yajun Duan
Yajun Duan received her Ph.D. from Nankai University in 2009 and then worked at Nankai University as a fellow until 2012 and as an associate professor until 2015. In 2015, she became a full professor at Hefei University of Technology in China. Her research interests include vascular biology, liver diseases, and metabolic syndrome.
Jihong Han
Jihong Han received his Ph.D. from the Medical College of Cornell University in 1995 and then worked at Mount Sinai Medical School as a postdoctoral fellow. From 1996 to 1999, he worked as a research associate and was promoted to an assistant professor in 1999 and an associate professor in 2004 at the Center of Vascular Biology, Weill Medical College of Cornell University. In 2007, he became a full professor at Nankai University. In 2015, he started working at Hefei University of Technology as a professor. His research interests include vascular biology, liver diseases, and cancer.
Chenzhong Liao
Chenzhong Liao received his Ph.D. from the Chinese Academy of Sciences in 2004 and then worked at Shenzhen Chipscreen Biosciences as a drug designer. From 2005 to 2010, he worked as a visiting fellow (postdoc) at the CADD group, Laboratory of Medicinal Chemistry (now Chemical Biology Laboratory), National Cancer Institute at Frederick, National Institutes of Health of the U.S. government. He then took two years working at the Department of Pathology, University of Michigan Medical School. In 2012, he became a full professor at the Department of Pharmaceutical Sciences and Engineering, Hefei University of Technology in China. His research interests include drug design, drug development, cheminformatics, and medicinal chemistry.
Acknowledgments
ARTICLE SECTIONS
This work was financially supported by the National Natural Science Foundation of China (21672050, 81803352) and Fundamental Research Funds for the Central Universities (JZ2020HGTB0052).
| Abbreviations Used | |
| AA | alopecia areata |
| Aβ | amyloid-β |
| AD | Alzheimer’s disease |
| AGC | protein kinase A, G, and C |
| AKT | protein kinase B |
| ALS | amyotrophic lateral sclerosis |
| AML | acute myeloid leukemia |
| APDS | activated PI3Kδ syndrome |
| AS | ankylosing spondylitis |
| ASK1 | apoptosis signal-regulating kinase 1 |
| βAR | β-adrenergic receptor |
| BTK | Bruton’s tyrosine kinase |
| CaMKII | calcium/calmodulin-dependent protein kinase II |
| CD | Crohn’s disease |
| CDK | cyclin-dependent kinase |
| CLL | chronic lymphocytic leukemia |
| CLK | cyclin-dependent-like kinase |
| CNS | central nervous system |
| COPD | chronic obstructive pulmonary disease |
| COVID-19 | coronavirus disease 2019 |
| CSF1R | colony-stimulating factor 1 receptor |
| CSU | chronic spontaneous urticaria |
| DC | dendritic cell |
| EGFR | epidermal growth factor receptor |
| FGFR | fibroblast growth factor receptor |
| FLT3 | FMS-like tyrosine kinase 3 |
| GRK | G protein-coupled receptor kinase |
| GSK3 | glycogen synthase kinase 3 |
| GVHD | graft versus host disease |
| IBD | inflammatory bowel disease |
| IL | interleukin |
| IPF | idiopathic pulmonary fibrosis |
| IRAK4 | interleukin-1 receptor-associated kinase |
| ITK | interleukin-2-inducible T-cell kinase |
| ITP | immune thrombocytopenia |
| JAK | Janus kinase |
| JH2 | pseudokinase domain |
| JNK | c-Jun-N-terminal kinase |
| KHK | ketohexokinase |
| KSHV | Kaposi sarcoma-associated herpesvirus |
| LBCL | large B-cell lymphoma |
| LPS | lipopolysaccharide |
| LRRK2 | leucine-rich repeat kinase 2 |
| mAb | monoclonal antibody |
| MAP3K | mitogen-activated protein kinase kinase kinase |
| MAPK | mitogen-activated protein kinase |
| MCL | mantle cell lymphoma |
| MK2 | p38/MAPK-activated kinase 2 |
| MS | multiple sclerosis |
| mTOR | mammalian target of rapamycin |
| mTORC | mTOR complex |
| NF-κB | nuclear factor κ light-chain-enhancer of activated B-cells |
| NGF | nerve growth factor |
| NHL | non-Hodgkin lymphoma |
| NIK | NF-κB inducing kinase |
| NOD | nucleotide oligomerization domain |
| NSCLC | nonsmall cell lung cancer |
| p38α MAPK | p38α mitogen-activated protein kinase |
| PA | psoriatic arthritis |
| PASLI | p110 δ activating mutation causing senescent T-cells, lymphadenopathy and immunodeficiency |
| PCV | polycythemia vera |
| PD | Parkinson’s disease |
| PDGFR | platelet-derived growth factor receptor |
| PDK1 | phosphoinositide-dependent protein kinase 1 |
| PfCDPK | Plasmodium falciparum calcium-dependent protein kinases |
| PfCLK3 | Plasmodium falciparum cyclin-dependent–like kinase |
| PfGSK3 | Plasmodium falciparum glycogen synthase kinase 3 |
| PfMRK | Plasmodium falciparum MO15-related kinase |
| PfPI4K | Plasmodium falciparum phosphatidylinositol 4-kinase |
| PfPKG | Plasmodium falciparum cGMP-dependent protein kinase |
| PI3K | phosphatidylinositol 3-kinase |
| PI4K | phosphatidylinositol 4-kinase |
| PIK | phosphoinositide lipid kinases |
| PKC | protein kinase C |
| PLK | polo-like kinase |
| PP | plaque psoriasis |
| PROTAC | proteolysis targeting chimera |
| PTCL | peripheral T-cell lymphoma |
| RA | rheumatoid arthritis |
| RIPK | receptor interacting protein kinase |
| ROCK | Rho-associated protein kinase |
| SLE | systemic lupus erythematosus |
| SMKI | small-molecule kinase inhibitor |
| SS | Sjögren’s syndrome |
| STAT | signal transducers and activators of transcription |
| SYK | spleen tyrosine kinase |
| TgCDPK1 | Toxoplasma gondii calcium dependent protein kinase 1 |
| TLR | toll-like receptor |
| TSC | tuberous sclerosis complex |
| TRK | tropomyosin receptor kinase |
| TNF | tumor necrosis factor |
| TYK2 | tyrosine kinase 2 |
| UC | ulcerative colitis |
| VEGF | vascular endothelial growth factor |
| VEGFR | vascular endothelial growth factor receptor |
| WM | Waldenström’s macroglobulinemia |
References
ARTICLE SECTIONS
This article references 359 other publications.
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- 14Punwani, N.; Scherle, P.; Flores, R.; Shi, J.; Liang, J.; Yeleswaram, S.; Levy, R.; Williams, W.; Gottlieb, A. Preliminary clinical activity of a topical JAK1/2 inhibitor in the treatment of psoriasis. J. Am. Acad. Dermatol. 2012, 67, 658– 664, DOI: 10.1016/j.jaad.2011.12.018[Crossref], [PubMed], [CAS], Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlOnsLrP&md5=9f1564cc0cc4726532aa0b4b5346d228Preliminary clinical activity of a topical JAK1/2 inhibitor in the treatment of psoriasisPunwani, Naresh; Scherle, Peggy; Flores, Robert; Shi, Jack; Liang, Jinjin; Yeleswaram, Swamy; Levy, Richard; Williams, William; Gottlieb, AliceJournal of the American Academy of Dermatology (2012), 67 (4), 658-664CODEN: JAADDB; ISSN:0190-9622. (Elsevier)Janus-assocd. kinases (JAKs) are involved in signal transduction from a variety of cytokines implicated in the pathogenesis of psoriasis, including interleukin (IL)-12, IL-23, and interferon-γ. INCB018424, a small mol. inhibitor of JAK1 and JAK2, inhibits cytokine-induced JAK/signal transducers and activators of transcription signaling and the resultant prodn. of inflammatory proteins (eg, IL-17). We sought to demonstrate proof of concept in patients with stable plaque psoriasis. Patients were dosed with vehicle, 0.5% or 1.0% INCB018424 phosphate cream once a day or 1.5% twice a day for 28 days. Addnl. groups included two active comparators (calcipotriene 0.005% cream or betamethasone dipropionate 0.05% cream). Both the 1% and the 1.5% cream improved lesion thickness, erythema, and scaling and reduced lesion area compared with placebo. A composite lesion score decreased by greater than 50% with the efficacious doses of INCB018424 compared with 32% for vehicle controls. Topical application of INCB018424 was well tolerated with few mild adverse events noted. Mean plasma concns. of INCB018424 after topical application of 0.5% to 1.5% cream were in the low nanomolar range, representing a fraction (<1%) of the half maximal inhibitory concn. (IC50) in whole blood for inhibition of cytokine-stimulated signal transducers and activators of transcription-3 phosphorylation. This study was limited by the relatively short study duration and small sample size. Topical INCB018424 is safe, is well tolerated, and exhibits clin. activity in the topical treatment of psoriasis.
- 15Bayart, C. B.; DeNiro, K. L.; Brichta, L.; Craiglow, B. G.; Sidbury, R. Topical Janus kinase inhibitors for the treatment of pediatric alopecia areata. J. Am. Acad. Dermatol. 2017, 77, 167– 170, DOI: 10.1016/j.jaad.2017.03.024[Crossref], [PubMed], [CAS], Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cnoslOitA%253D%253D&md5=8eb3104131bfeabeaed358e41d8a082bTopical Janus kinase inhibitors for the treatment of pediatric alopecia areataBayart Cheryl B; DeNiro Katherine L; Sidbury Robert; Brichta Lars; Craiglow Brittany GJournal of the American Academy of Dermatology (2017), 77 (1), 167-170 ISSN:.There is no expanded citation for this reference.
- 16Chrencik, J. E.; Patny, A.; Leung, I. K.; Korniski, B.; Emmons, T. L.; Hall, T.; Weinberg, R. A.; Gormley, J. A.; Williams, J. M.; Day, J. E.; Hirsch, J. L.; Kiefer, J. R.; Leone, J. W.; Fischer, H. D.; Sommers, C. D.; Huang, H. C.; Jacobsen, E. J.; Tenbrink, R. E.; Tomasselli, A. G.; Benson, T. E. Structural and thermodynamic characterization of the TYK2 and JAK3 kinase domains in complex with CP-690550 and CMP-6. J. Mol. Biol. 2010, 400, 413– 433, DOI: 10.1016/j.jmb.2010.05.020[Crossref], [PubMed], [CAS], Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXos1ylt7g%253D&md5=1b1efc3d6f913143dc9113e4ac1c4c60Structural and Thermodynamic Characterization of the TYK2 and JAK3 Kinase Domains in Complex with CP-690550 and CMP-6Chrencik, Jill E.; Patny, Akshay; Leung, Iris K.; Korniski, Brian; Emmons, Thomas L.; Hall, Troii; Weinberg, Robin A.; Gormley, Jennifer A.; Williams, Jennifer M.; Day, Jacqueline E.; Hirsch, Jeffrey L.; Kiefer, James R.; Leone, Joseph W.; Fischer, H. David; Sommers, Cynthia D.; Huang, Horng-Chih; Jacobsen, E. J.; Tenbrink, Ruth E.; Tomasselli, Alfredo G.; Benson, Timothy E.Journal of Molecular Biology (2010), 400 (3), 413-433CODEN: JMOBAK; ISSN:0022-2836. (Elsevier Ltd.)Janus kinases (JAKs) are crit. regulators of cytokine pathways and attractive targets of therapeutic value in both inflammatory and myeloproliferative diseases. Although the crystal structures of active JAK1 and JAK2 kinase domains have been reported recently with the clin. compd. CP-690550, the structures of both TYK2 and JAK3 with CP-690550 have remained outstanding. Here, we report the crystal structures of TYK2, a first in class structure, and JAK3 in complex with PAN-JAK inhibitors CP-690550 ((3R,4R)-3-[4-methyl-3-[N-methyl-N-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropionitrile) and CMP-6 (tetracyclic pyridone 2-t-butyl-9-fluoro-3,6-dihydro-7H-benz[h]-imidaz[4,5-f]isoquinoline-7-one), both of which bind in the ATP-binding cavities of both JAK isoenzymes in orientations similar to that obsd. in crystal structures of JAK1 and JAK2. Addnl., a complete thermodn. characterization of JAK/CP-690550 complex formation was completed by isothermal titrn. calorimetry, indicating the crit. role of the nitrile group from the CP-690550 compd. Finally, computational anal. using WaterMap further highlights the crit. positioning of the CP-690550 nitrile group in the displacement of an unfavorable water mol. beneath the glycine-rich loop. Taken together, the data emphasize the outstanding properties of the kinome-selective JAK inhibitor CP-690550, as well as the challenges in obtaining JAK isoenzyme-selective inhibitors due to the overall structural and sequence similarities between the TYK2, JAK1, JAK2 and JAK3 isoenzymes. Nevertheless, subtle amino acid variations of residues lining the ligand-binding cavity of the JAK enzymes, as well as the global positioning of the glycine-rich loop, might provide the initial clues to obtaining JAK-isoenzyme selective inhibitors.
- 17Moisan, A.; Lee, Y. K.; Zhang, J. D.; Hudak, C. S.; Meyer, C. A.; Prummer, M.; Zoffmann, S.; Truong, H. H.; Ebeling, M.; Kiialainen, A.; Gerard, R.; Xia, F.; Schinzel, R. T.; Amrein, K. E.; Cowan, C. A. White-to-brown metabolic conversion of human adipocytes by JAK inhibition. Nat. Cell Biol. 2015, 17, 57– 67, DOI: 10.1038/ncb3075[Crossref], [PubMed], [CAS], Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitV2nsrnK&md5=3b402af145e2806484068d374a93162fWhite-to-brown metabolic conversion of human adipocytes by JAK inhibitionMoisan, Annie; Lee, Youn-Kyoung; Zhang, Jitao David; Hudak, Carolyn S.; Meyer, Claas A.; Prummer, Michael; Zoffmann, Sannah; Truong, Hoa Hue; Ebeling, Martin; Kiialainen, Anna; Gerard, Regine; Xia, Fang; Schinzel, Robert T.; Amrein, Kurt E.; Cowan, Chad A.Nature Cell Biology (2015), 17 (1), 57-67CODEN: NCBIFN; ISSN:1465-7392. (Nature Publishing Group)The rising incidence of obesity and related disorders such as diabetes and heart disease has focused considerable attention on the discovery of new therapeutics. One promising approach has been to increase the no. or activity of brown-like adipocytes in white adipose depots, as this has been shown to prevent diet-induced obesity and reduce the incidence and severity of type 2 diabetes. Thus, the conversion of fat-storing cells into metabolically active thermogenic cells has become an appealing therapeutic strategy to combat obesity. Here, we report a screening platform for the identification of small mols. capable of promoting a white-to-brown metabolic conversion in human adipocytes. We identified two inhibitors of Janus kinase (JAK) activity with no precedent in adipose tissue biol. that stably confer brown-like metabolic activity to white adipocytes. Importantly, these metabolically converted adipocytes exhibit elevated UCP1 expression and increased mitochondrial activity. We further found that repression of interferon signalling and activation of hedgehog signalling in JAK-inactivated adipocytes contributes to the metabolic conversion obsd. in these cells. Our findings highlight a previously unknown role for the JAK-STAT pathway in the control of adipocyte function and establish a platform to identify compds. for the treatment of obesity.
- 18Al-Salama, Z. T.; Scott, L. J. Baricitinib: A Review in rheumatoid arthritis. Drugs 2018, 78, 761– 772, DOI: 10.1007/s40265-018-0908-4[Crossref], [PubMed], [CAS], Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXosFCrs7k%253D&md5=df956988c6927dd96c7fe5e547919dd3Baricitinib: A Review in Rheumatoid ArthritisAl-Salama, Zaina T.; Scott, Lesley J.Drugs (2018), 78 (7), 761-772CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)Baricitinib (Olumiant) is an oral, targeted synthetic DMARD that inhibits JAK1 and JAK2, which are implicated in the pathogenesis of rheumatoid arthritis (RA). This novel, small mol. is approved for use as monotherapy, or in combination with methotrexate, for the treatment of adults with moderate to severe active RA who responded inadequately to or were intolerant of ≥ 1 DMARD. In pivotal multinational trials, once-daily baricitinib 4 mg, with/without methotrexate (± another csDMARD), improved the signs and symptoms of RA, disease activity and phys. function in DMARD-naive patients and in patients with an inadequate response to methotrexate, csDMARDs or TNF inhibitors; baricitinib treatment also slowed structural joint damage in DMARD-naive patients and in those with an inadequate response to methotrexate and csDMARDs. Baricitinib plus methotrexate was more effective than adalimumab plus methotrexate in patients with an inadequate response to methotrexate. The onset of these benefits was generally rapid and sustained over time. Baricitinib was generally well tolerated during up to 5.5 years' treatment; the most commonly reported adverse drug reactions were upper respiratory tract infections, increased LDL cholesterol, nausea and thrombocytosis. Thus, once-daily baricitinib, as monotherapy or in combination with methotrexate, is an effective and generally well tolerated emerging treatment for patients with moderate to severe active RA who have responded inadequately to or are intolerant of ≥ 1 DMARD, and extends the options available for this population.
- 19Kunwar, S.; Collins, C. E.; Constantinescu, F. Baricitinib, a Janus kinase inhibitor, in the treatment of rheumatoid arthritis: a systematic literature review and meta-analysis of randomized controlled trials. Clin. Rheumatol. 2018, 37, 2611– 2620, DOI: 10.1007/s10067-018-4199-7[Crossref], [PubMed], [CAS], Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3c%252FotVOnuw%253D%253D&md5=663455a2aea96ec4b6c3f511e0dad888Baricitinib, a Janus kinase inhibitor, in the treatment of rheumatoid arthritis: a systematic literature review and meta-analysis of randomized controlled trialsKunwar Sumit; Collins Christopher E; Constantinescu FlorinaClinical rheumatology (2018), 37 (10), 2611-2620 ISSN:.Janus kinases (JAKs) play an important role in intracellular signaling for multiple cytokines in the pathogenesis of RA. Baricitinib is an oral, selective JAK 1 and 2 inhibitor which has been shown to be effective in the treatment of RA in several clinical trials. This meta-analysis aims to aggregate currently available data to assess the overall efficacy and safety of baricitinib in RA. We searched PubMed, EMBASE, and Cochrane CENTRAL from inception through 09/24/17 with restriction to English language. We excluded meeting abstracts without full text publication. We used RevMan 5.3 to perform meta-analysis between groups on baricitinib (2 and 4 mg daily) and placebo using random effect model calculating odds ratio (OR) as well as 95% confidence interval (CI). Compared to placebo, 2 mg of baricitinib was more effective in achieving ACR20 [54 vs. 36.6%; OR 2.09; 95% CI 1.60-2.71; p < 0.00001; I(2) 0%], ACR50 [31.6 vs. 10.3%; OR 2.3; 95% CI 1.68-3.15; p < 0.00001; I(2) 0%], and ACR70 responses [18.7 vs. 5.1%; OR 4.05; 95% CI 2.54-6.44; p < 0.00001; I(2) 0%]. Similarly, 4 mg of baricitinib daily was more effective than placebo. Baricitinib 2 mg once daily did not increase any adverse events [65.3 vs. 62.4%; OR 1.03; 95% CI 0.80-1.34; p = 0.8; I(2) 0%], serious adverse events [3.5 vs. 5%; OR 0.68; 95% CI 0.37-1.27; p = 0.22; I(2) 0%], and herpes zoster [1.2 vs. 0.4%; OR 2.34; 95% CI 0.27-20.47; p = 0.44; I(2) 37%] as compared to placebo. Similarly, 4 mg of baricitinib did not increase the risk of serious adverse events but increased herpes zoster infection [OR 3.88; 95% CI 1.36-11.06; p = 0.01; I(2) 0%] when compared to placebo. Baricitinib is effective in treatment of RA, and did not appear to have significant safety concerns during the first 6 months of treatment.
- 20Markham, A.; Keam, S. J. Peficitinib: first global approval. Drugs 2019, 79, 887– 891, DOI: 10.1007/s40265-019-01131-y[Crossref], [PubMed], [CAS], Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFWmtLzI&md5=eb2d2061829fc515854130050139871cPeficitinib: First Global ApprovalMarkham, Anthony; Keam, Susan J.Drugs (2019), 79 (8), 887-891CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)A review. Peficitinib [Smyraf (Astellas Pharma)] is a Janus kinase (JAK)1, JAK2, JAK3 and tyrosine kinase (Tyk)2 (pan-JAK) inhibitor recently approved in Japan for the treatment of rheumatoid arthritis. Inhibition of JAK suppresses the activation of cytokine signalling pathways involved in inflammation and joint destruction in rheumatoid arthritis. Peficitinib has been shown to significantly improve ACR20 and other measures of disease severity and to reduce the mean modified total Sharp score change from baseline in clin. trials. This article summarizes the milestones in the development of peficitinib leading to this first approval as a treatment for rheumatoid arthritis in patients who have an inadequate response to conventional therapies.
- 21Noji, S.; Hara, Y.; Miura, T.; Yamanaka, H.; Maeda, K.; Hori, A.; Yamamoto, H.; Obika, S.; Inoue, M.; Hase, Y.; Orita, T.; Doi, S.; Adachi, T.; Tanimoto, A.; Oki, C.; Kimoto, Y.; Ogawa, Y.; Negoro, T.; Hashimoto, H.; Shiozaki, M. Discovery of a janus kinase inhibitor bearing a highly three-dimensional spiro ccaffold: JTE-052 (Delgocitinib) as a new dermatological agent to treat inflammatory skin disorders. J. Med. Chem. 2020, 63, 7163– 7185, DOI: 10.1021/acs.jmedchem.0c00450[ACS Full Text], [CAS], Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtFWmsLrM&md5=f4eecf28446abb441f1436c41d8cb0a6Discovery of a Janus Kinase Inhibitor Bearing a Highly Three-Dimensional Spiro Scaffold: JTE-052 (Delgocitinib) as a New Dermatological Agent to Treat Inflammatory Skin DisordersNoji, Satoru; Hara, Yoshinori; Miura, Tomoya; Yamanaka, Hiroshi; Maeda, Katsuya; Hori, Akimi; Yamamoto, Hiroshi; Obika, Shingo; Inoue, Masafumi; Hase, Yasunori; Orita, Takuya; Doi, Satoki; Adachi, Tsuyoshi; Tanimoto, Atsuo; Oki, Chika; Kimoto, Yukari; Ogawa, Yoshihiro; Negoro, Tamotsu; Hashimoto, Hiromasa; Shiozaki, MakotoJournal of Medicinal Chemistry (2020), 63 (13), 7163-7185CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Dermatol. disorders such as atopic dermatitis arise from genetic and environmental causes and are complex and multifactorial in nature. Among possible risk factors, aberrant immunol. reactions are one of the leading etiologies. Immunosuppressive agents including topical steroids are common treatments for these disorders. Despite their reliability in clin. settings, topical steroids display side effects, typified by skin thinning. Accordingly, there is a need for alternate effective and well-tolerated therapies. As part of our efforts to investigate new immunomodulators, we have developed a series of JAK inhibitors, which incorporate novel three-dimensional spiro motifs and unexpectedly possess both excellent physicochem. properties and antidermatitis efficacy in the animal models. One of these compds., JTE-052 (ent-60), also known as delgocitinib, has been shown to be effective and well-tolerated in human clin. trials and has recently been approved in Japan for the treatment of atopic dermatitis as the first drug among Janus kinase inhibitors.
- 22Shan, S.; Zhou, Y.; Yu, J.; Yang, Q.; Pan, D.; Wang, Y.; Li, L.; Zhu, J.; Zhang, Y.; Huang, S.; Li, Z.; Ning, Z.; Xin, L.; Lu, X. Therapeutic treatment of a novel selective JAK3/JAK1/TBK1 inhibitor, CS12192, in rat and mouse models of rheumatoid arthritis. Int. Immunopharmacol. 2019, 77, 105914, DOI: 10.1016/j.intimp.2019.105914[Crossref], [PubMed], [CAS], Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitVaju7jE&md5=af003e55c8f149cd66b1632f19eb9f4dTherapeutic treatment of a novel selective JAK3/JAK1/TBK1 inhibitor, CS12192, in rat and mouse models of rheumatoid arthritisShan, Song; Zhou, You; Yu, Jindi; Yang, Qianjiao; Pan, Desi; Wang, Yanan; Li, Lingjie; Zhu, Jingzhong; Zhang, Yu; Huang, Shengjian; Li, Zhibin; Ning, Zhiqiang; Xin, Lijun; Lu, XianpingInternational Immunopharmacology (2019), 77 (), 105914CODEN: IINMBA; ISSN:1567-5769. (Elsevier B.V.)Rheumatoid arthritis (RA) is a representative autoimmune disease characterized by chronic inflammation and joint destruction. Although biol. inhibitors such as TNF-α and IL-6 antibodies have achieved success in clin. therapy, small mol. inhibitors against the Janus kinases (JAKs) involved in the signaling pathways of various cytokine receptors have gained more attraction as safe and efficacious options. In this study, we identified CS12192 as a novel selective JAK3/JAK1/TBK1 inhibitor and investigated its pharmacol. effects on the exptl. arthritis models in rat and mouse. We found that CS12192 showed a more selective inhibitory activity on JAK3, and to a less extent on JAK1 and TBK1, that were verified by decreased activation of p-STATs and p-IRF3 as well as down-regulation of IFN gene expression in the cultured cells with relevant stimuli. Furthermore, oral treatment with CS12192 dose-dependently ameliorated the disease severity, hind paw swelling, body wt. loss, and bone destruction in rat models of adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA). In a mouse CIA model, CS12192 also attenuated the disease severity, which was correlated with the suppressed CD4+ T cell activation and Th17 function, as well as the reduced cytokine levels in sera and pro-inflammatory cytokine and chemokine gene expression in joint tissue. Corroboratively, RANKL-induced osteoclast formation was inhibited by CS12192. Thus, these results suggest that CS12192 as a novel selective JAK inhibitor has therapeutic potential for the treatment of RA and may provide a new strategy for the control of autoimmune diseases.
- 23Fleischmann, R. Novel small-molecular therapeutics for rheumatoid arthritis. Curr. Opin. Rheumatol. 2012, 24, 335– 341, DOI: 10.1097/BOR.0b013e32835190ef[Crossref], [PubMed], [CAS], Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XkvFOmsLk%253D&md5=46627d79c7fe388c3a9d0fe05d83b040Novel small-molecular therapeutics for rheumatoid arthritisFleischmann, RoyCurrent Opinion in Rheumatology (2012), 24 (3), 335-341CODEN: CORHES; ISSN:1040-8711. (Lippincott Williams & Wilkins)Purpose of review: Since the introduction of biol. therapies into the treatment paradigm of rheumatoid arthritis (RA), there has been hope that oral small mol. immune modulators would be developed that would have a risk : benefit profile at least similar to biol. therapies, be more convenient for the patient and, hopefully, be less expensive. This article reviews the progress made in the development of these compds. over the past year. Recent findings: Addnl. information has become available in the past year on five oral compds. including kinase inhibitors (tofacitinib, fostamatinib, VX-509), an S1P lyase inhibitor (LX 3305) and a chemokine receptor-1 antagonist (CCX354-C). Efficacy has been shown in phase III with tofacitinib and in phase II with fostamatinib and VX-509; safety was the primary endpoint of the trials of CCX354-C and LX3305. Regarding side effects, liver test elevation and neutropenia occurred with tofacitinib, VX-509 and fostamatinib; lipid elevation with tofacitinib and VX-509; creatinine elevation and anemia with tofacitinib, and hypertension and diarrhea with fostamatinib. Summary: Compds. that inhibit tyrosine kinase pathways involved in cellular signalling have been shown to be effective in the treatment of RA with a reasonable risk : benefit ratio. It is too early to tell about inhibitors of other pathways.
- 24Bach, J.; Eastwood, P.; Gonzalez, J.; Gomez, E.; Alonso, J. A.; Fonquerna, S.; Lozoya, E.; Orellana, A.; Maldonado, M.; Calaf, E.; Alberti, J.; Perez, J.; Andres, A.; Prats, N.; Carreno, C.; Calama, E.; De Alba, J.; Calbet, M.; Miralpeix, M.; Ramis, I. Identification of 2-imidazopyridine and 2-aminopyridone purinones as potent pan-janus kinase (JAK) inhibitors for the inhaled treatment of respiratory diseases. J. Med. Chem. 2019, 62, 9045– 9060, DOI: 10.1021/acs.jmedchem.9b00533[ACS Full Text], [CAS], Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFCrs7%252FN&md5=39115f5f662922242340abd04394ffd8Identification of 2-Imidazopyridine and 2-Aminopyridone Purinones as Potent Pan-Janus Kinase (JAK) Inhibitors for the Inhaled Treatment of Respiratory DiseasesBach, Jordi; Eastwood, Paul; Gonzalez, Jacob; Gomez, Elena; Alonso, Juan Antonio; Fonquerna, Silvia; Lozoya, Estrella; Orellana, Adela; Maldonado, Monica; Calaf, Elena; Alberti, Joan; Perez, Juan; Andres, Ana; Prats, Neus; Carreno, Cristina; Calama, Elena; De Alba, Jorge; Calbet, Marta; Miralpeix, Montserrat; Ramis, IsabelJournal of Medicinal Chemistry (2019), 62 (20), 9045-9060CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Janus kinases (JAKs) have a key role in regulating the expression and function of relevant inflammatory cytokines involved in asthma and chronic obstructive pulmonary disease. Herein are described the design, synthesis, and pharmacol. evaluation of a series of novel purinone JAK inhibitors with profiles suitable for inhaled administration. Replacement of the imidazopyridine hinge binding motif present in the initial compds. of this series with a pyridone ring resulted in the mitigation of cell cytotoxicity. Further systematic structure-activity relationship (SAR) efforts driven by structural biol. studies led to the discovery of pyridone I, a potent pan-JAK inhibitor with good selectivity, long lung retention time, low oral bioavailability, and proven efficacy in the lipopolysaccharide-induced rat model of airway inflammation by the inhaled route.
- 25Farmer, L. J.; Ledeboer, M. W.; Hoock, T.; Arnost, M. J.; Bethiel, R. S.; Bennani, Y. L.; Black, J. J.; Brummel, C. L.; Chakilam, A.; Dorsch, W. A.; Fan, B.; Cochran, J. E.; Halas, S.; Harrington, E. M.; Hogan, J. K.; Howe, D.; Huang, H.; Jacobs, D. H.; Laitinen, L. M.; Liao, S.; Mahajan, S.; Marone, V.; Martinez-Botella, G.; McCarthy, P.; Messersmith, D.; Namchuk, M.; Oh, L.; Penney, M. S.; Pierce, A. C.; Raybuck, S. A.; Rugg, A.; Salituro, F. G.; Saxena, K.; Shannon, D.; Shlyakter, D.; Swenson, L.; Tian, S. K.; Town, C.; Wang, J.; Wang, T.; Wannamaker, M. W.; Winquist, R. J.; Zuccola, H. J. Discovery of VX-509 (Decernotinib): a potent and selective janus kinase 3 inhibitor for the treatment of autoimmune diseases. J. Med. Chem. 2015, 58, 7195– 7216, DOI: 10.1021/acs.jmedchem.5b00301[ACS Full Text], [CAS], Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1KmsbbO&md5=8ba1e0beb7570baaf68fd5f20b54f9f9Discovery of VX-509 (Decernotinib): A Potent and Selective Janus Kinase 3 Inhibitor for the Treatment of Autoimmune DiseasesFarmer, Luc J.; Ledeboer, Mark W.; Hoock, Thomas; Arnost, Michael J.; Bethiel, Randy S.; Bennani, Youssef L.; Black, James J.; Brummel, Christopher L.; Chakilam, Ananthsrinivas; Dorsch, Warren A.; Fan, Bin; Cochran, John E.; Halas, Summer; Harrington, Edmund M.; Hogan, James K.; Howe, David; Huang, Hui; Jacobs, Dylan H.; Laitinen, Leena M.; Liao, Shengkai; Mahajan, Sudipta; Marone, Valerie; Martinez-Botella, Gabriel; McCarthy, Pamela; Messersmith, David; Namchuk, Mark; Oh, Luke; Penney, Marina S.; Pierce, Albert C.; Raybuck, Scott A.; Rugg, Arthur; Salituro, Francesco G.; Saxena, Kumkum; Shannon, Dean; Shlyakter, Dina; Swenson, Lora; Tian, Shi-Kai; Town, Christopher; Wang, Jian; Wang, Tiansheng; Wannamaker, M. Woods; Winquist, Raymond J.; Zuccola, Harmon J.Journal of Medicinal Chemistry (2015), 58 (18), 7195-7216CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)While several therapeutic options exist, the need for more effective, safe, and convenient treatment for a variety of autoimmune diseases persists. Targeting the Janus tyrosine kinases (JAKs), which play essential roles in cell signaling responses and can contribute to aberrant immune function assocd. with disease, has emerged as a novel and attractive approach for the development of new autoimmune disease therapies. We screened our compd. library against JAK3, a key signaling kinase in immune cells, and identified multiple scaffolds showing good inhibitory activity for this kinase. A particular scaffold of interest, the 1H-pyrrolo[2,3-b]pyridine series (7-azaindoles), was selected for further optimization in part on the basis of binding affinity (Ki) as well as on the basis of cellular potency. Optimization of this chem. series led to the identification of VX-509 (decernotinib), a novel, potent, and selective JAK3 inhibitor, which demonstrates good efficacy in vivo in the rat host vs. graft model (HvG). On the basis of these findings, it appears that VX-509 offers potential for the treatment of a variety of autoimmune diseases.
- 26Chang, Y.; Xu, S.; Ding, K. Tyrosine kinase 2 (TYK2) allosteric inhibitors to treat autoimmune diseases. J. Med. Chem. 2019, 62, 8951– 8952, DOI: 10.1021/acs.jmedchem.9b01612[ACS Full Text], [CAS], Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFeqtrjK&md5=d8214c7fca197889246df48f29e5c5e5Tyrosine Kinase 2 (TYK2) Allosteric Inhibitors To Treat Autoimmune DiseasesChang, Yu; Xu, Shilin; Ding, KeJournal of Medicinal Chemistry (2019), 62 (20), 8951-8952CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. TYK2 is an emerging drug target for various human autoimmune diseases. However, discovery of selective TYK2 inhibitor over other JAK family members (i.e., JAK1, 2, 3) by targeting the catalytically active site (Janus Homolog 1 (JH1) domain) is challenging. This Viewpoint discusses the discovery of a series of N-Me pyridazine-3-carboxamides as novel selective pseudokinase (JH2) domain binders of TYK2. A systematic structure-based optimization yielded a highly potent and selective allosteric TYK2 inhibitor candidate that is currently in phase III clin. trial for psoriasis.
- 27Moslin, R.; Zhang, Y.; Wrobleski, S. T.; Lin, S.; Mertzman, M.; Spergel, S.; Tokarski, J. S.; Strnad, J.; Gillooly, K.; McIntyre, K. W.; Zupa-Fernandez, A.; Cheng, L.; Sun, H.; Chaudhry, C.; Huang, C.; D’Arienzo, C.; Heimrich, E.; Yang, X.; Muckelbauer, J. K.; Chang, C.; Tredup, J.; Mulligan, D.; Xie, D.; Aranibar, N.; Chiney, M.; Burke, J. R.; Lombardo, L.; Carter, P. H.; Weinstein, D. S. Identification of N-methyl nicotinamide and N-methyl pyridazine-3-carboxamide pseudokinase domain ligands as highly selective allosteric inhibitors of tyrosine kinase 2 (TYK2). J. Med. Chem. 2019, 62, 8953– 8972, DOI: 10.1021/acs.jmedchem.9b00443[ACS Full Text], [CAS], Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtlOltbrO&md5=869bfe303f0743867b8c9eb8201707c3Identification of N-Methyl Nicotinamide and N-Methyl Pyridazine-3-Carboxamide Pseudokinase Domain Ligands as Highly Selective Allosteric Inhibitors of Tyrosine Kinase 2 (TYK2)Moslin, Ryan; Zhang, Yanlei; Wrobleski, Stephen T.; Lin, Shuqun; Mertzman, Michael; Spergel, Steven; Tokarski, John S.; Strnad, Joann; Gillooly, Kathleen; McIntyre, Kim W.; Zupa-Fernandez, Adriana; Cheng, Lihong; Sun, Huadong; Chaudhry, Charu; Huang, Christine; D'Arienzo, Celia; Heimrich, Elizabeth; Yang, Xiaoxia; Muckelbauer, Jodi K.; Chang, ChiehYing; Tredup, Jeffrey; Mulligan, Dawn; Xie, Dianlin; Aranibar, Nelly; Chiney, Manoj; Burke, James R.; Lombardo, Louis; Carter, Percy H.; Weinstein, David S.Journal of Medicinal Chemistry (2019), 62 (20), 8953-8972CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)As a member of the Janus (JAK) family of nonreceptor tyrosine kinases, TYK2 plays an important role in mediating the signaling of pro-inflammatory cytokines including IL-12, IL-23, and type 1 interferons. The nicotinamide 4, identified by a SPA-based high-throughput screen targeting the TYK2 pseudokinase domain, potently inhibits IL-23 and IFNα signaling in cellular assays. The described work details the optimization of this poorly selective hit (4) to potent and selective mols. such as 47 and 48. The discoveries described herein were crit. to the eventual identification of the clin. TYK2 JH2 inhibitor (see following report in this issue). Compd. 48 provided robust inhibition in a mouse IL-12-induced IFNγ pharmacodynamic model as well as efficacy in an IL-23 and IL-12-dependent mouse colitis model. These results demonstrate the ability of TYK2 JH2 domain binders to provide a highly selective alternative to conventional TYK2 orthosteric inhibitors.
- 28Wrobleski, S. T.; Moslin, R.; Lin, S.; Zhang, Y.; Spergel, S.; Kempson, J.; Tokarski, J. S.; Strnad, J.; Zupa-Fernandez, A.; Cheng, L.; Shuster, D.; Gillooly, K.; Yang, X.; Heimrich, E.; McIntyre, K. W.; Chaudhry, C.; Khan, J.; Ruzanov, M.; Tredup, J.; Mulligan, D.; Xie, D.; Sun, H.; Huang, C.; D’Arienzo, C.; Aranibar, N.; Chiney, M.; Chimalakonda, A.; Pitts, W. J.; Lombardo, L.; Carter, P. H.; Burke, J. R.; Weinstein, D. S. Highly selective inhibition of tyrosine kinase 2 (TYK2) for the treatment of autoimmune diseases: discovery of the allosteric inhibitor BMS-986165. J. Med. Chem. 2019, 62, 8973– 8995, DOI: 10.1021/acs.jmedchem.9b00444[ACS Full Text], [CAS], Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtlyht7%252FP&md5=ca161c470df002b0bdd2bf6b19920adaHighly Selective Inhibition of Tyrosine Kinase 2 (TYK2) for the Treatment of Autoimmune Diseases: Discovery of the Allosteric Inhibitor BMS-986165Wrobleski, Stephen T.; Moslin, Ryan; Lin, Shuqun; Zhang, Yanlei; Spergel, Steven; Kempson, James; Tokarski, John S.; Strnad, Joann; Zupa-Fernandez, Adriana; Cheng, Lihong; Shuster, David; Gillooly, Kathleen; Yang, Xiaoxia; Heimrich, Elizabeth; McIntyre, Kim W.; Chaudhry, Charu; Khan, Javed; Ruzanov, Max; Tredup, Jeffrey; Mulligan, Dawn; Xie, Dianlin; Sun, Huadong; Huang, Christine; D'Arienzo, Celia; Aranibar, Nelly; Chiney, Manoj; Chimalakonda, Anjaneya; Pitts, William J.; Lombardo, Louis; Carter, Percy H.; Burke, James R.; Weinstein, David S.Journal of Medicinal Chemistry (2019), 62 (20), 8973-8995CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Small mol. JAK inhibitors have emerged as a major therapeutic advancement in treating autoimmune diseases. The discovery of isoform selective JAK inhibitors that traditionally target the catalytically active site of this kinase family has been a formidable challenge. Our strategy to achieve high selectivity for TYK2 relies on targeting the TYK2 pseudokinase (JH2) domain. Herein we report the late stage optimization efforts including a structure-guided design and water displacement strategy that led to the discovery of BMS-986165 (11, I) as a high affinity JH2 ligand and potent allosteric inhibitor of TYK2. In addn. to unprecedented JAK isoform and kinome selectivity, I shows excellent pharmacokinetic properties with minimal profiling liabilities and is efficacious in several murine models of autoimmune disease. On the basis of these findings, I appears differentiated from all other reported JAK inhibitors and has been advanced as the first pseudokinase-directed therapeutic in clin. development as an oral treatment for autoimmune diseases.
- 29Feng, Y.; Duan, W.; Cu, X.; Liang, C.; Xin, M. Bruton’s tyrosine kinase (BTK) inhibitors in treating cancer: a patent review (2010–2018). Expert Opin. Ther. Pat. 2019, 29, 217– 241, DOI: 10.1080/13543776.2019.1594777[Crossref], [PubMed], [CAS], Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXnt1Wrsbo%253D&md5=2f31c214c46945f7818532a39430ec00Bruton's tyrosine kinase (BTK) inhibitors in treating cancer: a patent review (2010-2018)Feng, Yifan; Duan, Weiming; Cu, Xiaochuan; Liang, Chengyuan; Xin, MinhangExpert Opinion on Therapeutic Patents (2019), 29 (4), 217-241CODEN: EOTPEG; ISSN:1354-3776. (Taylor & Francis Ltd.)A review. Bruton's tyrosine kinase (BTK) plays a crit. role in the regulation of survival, proliferation, activation and differentiation of B-lineage cells. It participates by regulating multiple cellular signaling pathways, including B cell receptor and FcR signaling cascades. BTK is abundantly expressed and constitutively active in the pathogenesis of B cell hematol. malignancies, as well as several autoimmune diseases. Therefore, BTK is considered as an attractive target for treatment of B-lineage lymphomas, leukemias, and some autoimmune diseases. Many industry and academia efforts have been made to explore small mol. BTK inhibitors. This review aims to provide an overview of the patented BTK inhibitors for the treatment of cancer from 2010 to 2018. BTK inhibitors attract much interest for their therapeutic potential in the treatment of cancers and autoimmune diseases, esp. for B cell hematol. malignancies. In 2013, ibrutinib was approved by the FDA as the first-in-class BTK inhibitors for the treatment of mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), and now it is also undergoing clin. evaluation for other indications in either single or combined therapy. It is clear that BTK inhibitors can provide a promising clin. benefit in treating B-lineage lymphomas and leukemias.
- 30Rip, J.; Van Der Ploeg, E. K.; Hendriks, R. W.; Corneth, O. B. J. The role of Bruton’s tyrosine kinase in immune cell signaling and systemic autoimmunity. Crit. Rev. Immunol. 2018, 38, 17– 62, DOI: 10.1615/CritRevImmunol.2018025184[Crossref], [PubMed], [CAS], Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MjovFWksw%253D%253D&md5=0aad71e4f9349f97b7d81eb2739931dfThe Role of Bruton's Tyrosine Kinase in Immune Cell Signaling and Systemic AutoimmunityRip Jasper; Van Der Ploeg Esmee K; Hendriks Rudi W; Corneth Odilia B JCritical reviews in immunology (2018), 38 (1), 17-62 ISSN:1040-8401.Bruton's tyrosine kinase (BTK) is an intracellular signaling molecule first identified as the molecule affected in X-linked agammaglobulinemia (XLA) patients, who almost completely lack peripheral B cells and serum immunoglobulins. BTK is crucial for B cell development and various B cell functions, including cytokine and natural antibody production. Importantly, it is also expressed in numerous other cells, including monocytes, macrophages, granulocytes, dendritic cells, and osteoclasts. A few rare cases of autoimmune disease in XLA patients have been described. Interestingly, increased BTK protein expression in patients with systemic autoimmune disease appears to be correlated with autoantibody production. In addition, BTK may promote autoimmunity as an important driver of an imbalance in B-T cell interaction. Because of this overwhelming evidence of a pathogenic role of BTK in autoimmunity, several clinical trials in rheumatoid arthritis and systemic lupus erythematosus patients with BTK inhibitors are currently running. Here, we review BTK function in different signaling pathways and in different cell lineages, focusing on the growing body of literature indicating a critical role for BTK in autoimmunity. We also discuss BTK and the promising results of BTK inhibition in animal models of autoimmune disease.
- 31Di Paolo, J. A.; Huang, T.; Balazs, M.; Barbosa, J.; Barck, K. H.; Bravo, B. J.; Carano, R. A.; Darrow, J.; Davies, D. R.; DeForge, L. E.; Diehl, L.; Ferrando, R.; Gallion, S. L.; Giannetti, A. M.; Gribling, P.; Hurez, V.; Hymowitz, S. G.; Jones, R.; Kropf, J. E.; Lee, W. P.; Maciejewski, P. M.; Mitchell, S. A.; Rong, H.; Staker, B. L.; Whitney, J. A.; Yeh, S.; Young, W. B.; Yu, C.; Zhang, J.; Reif, K.; Currie, K. S. Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis. Nat. Chem. Biol. 2011, 7, 41– 50, DOI: 10.1038/nchembio.481[Crossref], [PubMed], [CAS], Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVOrsLjP&md5=99d925c71bc1b201191ebde0f1c0b50fSpecific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritisDi Paolo, Julie A.; Huang, Tao; Balazs, Mercedesz; Barbosa, James; Barck, Kai H.; Bravo, Brandon J.; Carano, Richard A. D.; Darrow, James; Davies, Douglas R.; DeForge, Laura E.; Diehl, Lauri; Ferrando, Ronald; Gallion, Steven L.; Giannetti, Anthony M.; Gribling, Peter; Hurez, Vincent; Hymowitz, Sarah G.; Jones, Randall; Kropf, Jeffrey E.; Lee, Wyne P.; Maciejewski, Patricia M.; Mitchell, Scott A.; Rong, Hong; Staker, Bart L.; Whitney, J. Andrew; Yeh, Sherry; Young, Wendy B.; Yu, Christine; Zhang, Juan; Reif, Karin; Currie, Kevin S.Nature Chemical Biology (2011), 7 (1), 41-50CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)Bruton's tyrosine kinase (Btk) is a therapeutic target for rheumatoid arthritis, but the cellular and mol. mechanisms by which Btk mediates inflammation are poorly understood. Here we describe the discovery of CGI1746, a small-mol. Btk inhibitor chemotype with a new binding mode that stabilizes an inactive nonphosphorylated enzyme conformation. CGI1746 has exquisite selectivity for Btk and inhibits both auto- and transphosphorylation steps necessary for enzyme activation. Using CGI1746, we demonstrate that Btk regulates inflammatory arthritis by two distinct mechanisms. CGI1746 blocks B cell receptor-dependent B cell proliferation and in prophylactic regimens reduces autoantibody levels in collagen-induced arthritis. In macrophages, Btk inhibition abolishes FcγRIII-induced TNFα, IL-1β and IL-6 prodn. Accordingly, in myeloid- and FcγR-dependent autoantibody-induced arthritis, CGI1746 decreases cytokine levels within joints and ameliorates disease. These results provide new understanding of the function of Btk in both B cell- or myeloid cell-driven disease processes and provide a compelling rationale for targeting Btk in rheumatoid arthritis.
- 32Liang, C.; Tian, D.; Ren, X.; Ding, S.; Jia, M.; Xin, M.; Thareja, S. The development of Bruton’s tyrosine kinase (BTK) inhibitors from 2012 to 2017: A mini-review. Eur. J. Med. Chem. 2018, 151, 315– 326, DOI: 10.1016/j.ejmech.2018.03.062[Crossref], [PubMed], [CAS], Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXnt1ehtL0%253D&md5=1ea0bf36d8ebadbfba624f858911b182The development of Bruton's tyrosine kinase (BTK) inhibitors from 2012 to 2017: A mini-reviewLiang, Chengyuan; Tian, Danni; Ren, Xiaodong; Ding, Shunjun; Jia, Minyi; Xin, Minhang; Thareja, SureshEuropean Journal of Medicinal Chemistry (2018), 151 (), 315-326CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)A review. Bruton's tyrosine kinase (BTK) has emerged as a promising drug target for multiple diseases, particularly hematopoietic malignancies and autoimmune diseases related to B lymphocytes. This review focuses on the diverse, small-mol. inhibitors of BTK kinase that have shown good prospects for clin. application. Individual examples of these inhibitors, including both reversible and irreversible inhibitors and a recently developed reversible covalent inhibitor of BTK, are discussed. Considerable progress has been made in the development of irreversible inhibitors, most of which target the SH3 pocket and the cysteine 481 residue of BTK. The present review also surveys the pharmacol. advantages and deficiencies of both reversible and irreversible BTK drugs, with a focus on the structure-activity relationship (SARs) and binding modes of representative drugs, which could inspire crit. thinking and new ideas for developing potent BTK inhibitors with less unwanted off-target effects.
- 33Akinleye, A.; Chen, Y.; Mukhi, N.; Song, Y.; Liu, D. Ibrutinib and novel BTK inhibitors in clinical development. J. Hematol. Oncol. 2013, 6, 59, DOI: 10.1186/1756-8722-6-59[Crossref], [PubMed], [CAS], Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVagtrjI&md5=e5067b998c61818e2efbb62da935b490Ibrutinib and novel BTK inhibitors in clinical developmentAkinleye, Akintunde; Chen, Yamei; Mukhi, Nikhil; Song, Yongping; Liu, DelongJournal of Hematology & Oncology (2013), 6 (), 59CODEN: JHOOAO; ISSN:1756-8722. (BioMed Central Ltd.)A review. Small mol. inhibitors targeting dysregulated pathways (RAS/RAF/MEK, PI3K/AKT/mTOR, JAK/STAT) have significantly improved clin. outcomes in cancer patients. Recently Bruton's tyrosine kinase (BTK), a crucial terminal kinase enzyme in the B-cell antigen receptor (BCR) signaling pathway, has emerged as an attractive target for therapeutic intervention in human malignancies and autoimmune disorders. Ibrutinib, a novel first-in-human BTK inhibitor, has demonstrated clin. effectiveness and tolerability in early clin. trials and has progressed into phase III trials. However, addnl. research is necessary to identify the optimal dosing schedule, as well as patients most likely to benefit from BTK inhibition. This review summarizes preclin. and clin. development of ibrutinib and other novel BTK inhibitors (GDC-0834, CGI-560, CGI-1746, HM-71224, CC-292 and ONO-4059, CNX-774, LFM-A13) in the treatment of B-cell malignancies and autoimmune disorders.
- 34de Weerdt, I.; Koopmans, S. M.; Kater, A. P.; van Gelder, M. Incidence and management of toxicity associated with ibrutinib and idelalisib: a practical approach. Haematologica 2017, 102, 1629– 1639, DOI: 10.3324/haematol.2017.164103[Crossref], [PubMed], [CAS], Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitV2js7jE&md5=63198531f21c5cc5ca64ead536e5684aIncidence and management of toxicity associated with ibrutinib and idelalisib: a practical approachde Weerdt, Iris; Koopmans, Suzanne M.; Kater, Arnon P.; Van Gelder, MichelHaematologica (2017), 102 (10), 1629-1639CODEN: HAEMAX; ISSN:1592-8721. (Ferrata Storti Foundation)The use of novel B-cell receptor signaling inhibitors results in high response rates and long progression-free survival in patients with indolent B-cell malignancies, such as chronic lymphocytic leukemia, follicular lymphoma, mantle cell lymphoma and Waldenstrom macroglobulinemia. Ibrutinib, the first-in-class inhibitor of Bruton tyrosine kinase, and idelalisib, the first-in-class inhibitor of phosphatidylinositol 3-kinase α, have recently been approved for the treatment of several indolent B-cell malignancies. These drugs are esp. being used for previously unmet needs, i.e., for patients with relapsed or refractory disease, high-risk cytogenetic or mol. abnormalities, or with comorbidities. Treatment with ibrutinib and idelalisib is generally well tolerated, even by elderly patients. However, the use of these drugs may come with toxicities that are distinct from the side effects of immunochemotherapy. In this review we discuss the most commonly reported and/or most clin. relevant adverse events assocd. with these B-cell receptor inhibitors, with special emphasis on recommendations for their management.
- 35Wu, J.; Zhang, M.; Liu, D. Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. J. Hematol. Oncol. 2016, 9, 21, DOI: 10.1186/s13045-016-0250-9[Crossref], [PubMed], [CAS], Google Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXis1eisrw%253D&md5=a6a8f9b9236abe7ef1054a41e1c71e5aAcalabrutinib (ACP-196): a selective second-generation BTK inhibitorWu, Jingjing; Zhang, Mingzhi; Liu, DelongJournal of Hematology & Oncology (2016), 9 (), 21/1-21/4CODEN: JHOOAO; ISSN:1756-8722. (BioMed Central Ltd.)More and more targeted agents become available for B cell malignancies with increasing precision and potency. The first-in-class Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, has been in clin. use for the treatment of chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's macroglobulinemia. More selective BTK inhibitors (ACP-196, ONO/GS-4059, BGB-3111, CC-292) are being explored. Acalabrutinib (ACP-196) is a novel irreversible second-generation BTK inhibitor that was shown to be more potent and selective than ibrutinib. This review summarized the preclin. research and clin. data of acalabrutinib.
- 36Guo, Y.; Liu, Y.; Hu, N.; Yu, D.; Zhou, C.; Shi, G.; Zhang, B.; Wei, M.; Liu, J.; Luo, L.; Tang, Z.; Song, H.; Guo, Y.; Liu, X.; Su, D.; Zhang, S.; Song, X.; Zhou, X.; Hong, Y.; Chen, S.; Cheng, Z.; Young, S.; Wei, Q.; Wang, H.; Wang, Q.; Lv, L.; Wang, F.; Xu, H.; Sun, H.; Xing, H.; Li, N.; Zhang, W.; Wang, Z.; Liu, G.; Sun, Z.; Zhou, D.; Li, W.; Liu, L.; Wang, L.; Wang, Z. Discovery of Zanubrutinib (BGB-3111), a novel, potent, and selective covalent inhibitor of Bruton’s tyrosine kinase. J. Med. Chem. 2019, 62, 7923– 7940, DOI: 10.1021/acs.jmedchem.9b00687[ACS Full Text], [CAS], Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsFSku7bP&md5=5cdb551d296e60eb1e82b03b7a0384eeDiscovery of Zanubrutinib (BGB-3111), a Novel, Potent, and Selective Covalent Inhibitor of Bruton's Tyrosine KinaseGuo, Yunhang; Liu, Ye; Hu, Nan; Yu, Desheng; Zhou, Changyou; Shi, Gongyin; Zhang, Bo; Wei, Min; Liu, Junhua; Luo, Lusong; Tang, Zhiyu; Song, Huipeng; Guo, Yin; Liu, Xuesong; Su, Dan; Zhang, Shuo; Song, Xiaomin; Zhou, Xing; Hong, Yuan; Chen, Shuaishuai; Cheng, Zhenzhen; Young, Steve; Wei, Qiang; Wang, Haisheng; Wang, Qiuwen; Lv, Lei; Wang, Fan; Xu, Haipeng; Sun, Hanzi; Xing, Haimei; Li, Na; Zhang, Wei; Wang, Zhongbo; Liu, Guodong; Sun, Zhijian; Zhou, Dongping; Li, Wei; Liu, Libin; Wang, Lai; Wang, ZhiweiJournal of Medicinal Chemistry (2019), 62 (17), 7923-7940CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Aberrant activation of Bruton's tyrosine kinase (BTK) plays an important role in pathogenesis of B-cell lymphomas, suggesting that inhibition of BTK is useful in the treatment of hematol. malignancies. The discovery of a more selective on-target covalent BTK inhibitor is of high value. Herein, we disclose the discovery and preclin. characterization of a potent, selective, and irreversible BTK inhibitor as our clin. candidate by using in vitro potency, selectivity, pharmacokinetics (PK), and in vivo pharmacodynamic for prioritizing compds. Compd. BGB-3111 (31a, Zanubrutinib) demonstrates (i) potent activity against BTK and excellent selectivity over other TEC, EGFR and Src family kinases, (ii) desirable ADME, excellent in vivo pharmacodynamic in mice and efficacy in OCI-LY10 xenograft models.
- 37Caldwell, R. D.; Qiu, H.; Askew, B. C.; Bender, A. T.; Brugger, N.; Camps, M.; Dhanabal, M.; Dutt, V.; Eichhorn, T.; Gardberg, A. S.; Goutopoulos, A.; Grenningloh, R.; Head, J.; Healey, B.; Hodous, B. L.; Huck, B. R.; Johnson, T. L.; Jones, C.; Jones, R. C.; Mochalkin, I.; Morandi, F.; Nguyen, N.; Meyring, M.; Potnick, J. R.; Santos, D. C.; Schmidt, R.; Sherer, B.; Shutes, A.; Urbahns, K.; Follis, A. V.; Wegener, A. A.; Zimmerli, S. C.; Liu-Bujalski, L. Discovery of evobrutinib: an oral, potent, and highly selective, covalent Bruton’s tyrosine kinase (BTK) inhibitor for the treatment of immunological diseases. J. Med. Chem. 2019, 62, 7643– 7655, DOI: 10.1021/acs.jmedchem.9b00794[ACS Full Text], [CAS], Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsV2jtr7P&md5=f9711d8a18803afc356dbac848067acfDiscovery of Evobrutinib: An Oral, Potent, and Highly Selective, Covalent Bruton's Tyrosine Kinase (BTK) Inhibitor for the Treatment of Immunological DiseasesCaldwell, Richard D.; Qiu, Hui; Askew, Ben C.; Bender, Andrew T.; Brugger, Nadia; Camps, Montserrat; Dhanabal, Mohanraj; Dutt, Vikram; Eichhorn, Thomas; Gardberg, Anna S.; Goutopoulos, Andreas; Grenningloh, Roland; Head, Jared; Healey, Brian; Hodous, Brian L.; Huck, Bayard R.; Johnson, Theresa L.; Jones, Christopher; Jones, Reinaldo C.; Mochalkin, Igor; Morandi, Federica; Nguyen, Ngan; Meyring, Michael; Potnick, Justin R.; Santos, Dusica Cvetinovic; Schmidt, Ralf; Sherer, Brian; Shutes, Adam; Urbahns, Klaus; Follis, Ariele Viacava; Wegener, Ansgar A.; Zimmerli, Simone C.; Liu-Bujalski, LesleyJournal of Medicinal Chemistry (2019), 62 (17), 7643-7655CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Bruton's tyrosine kinase (BTK) inhibitors such as ibrutinib hold a prominent role in the treatment of B cell malignancies. However, further refinement is needed to this class of agents, particularly in terms of adverse events (potentially driven by kinase promiscuity), which preclude their evaluation in nononcol. indications. Here, we report the discovery and preclin. characterization of evobrutinib, a potent, obligate covalent inhibitor with high kinase selectivity. Evobrutinib displayed sufficient preclin. pharmacokinetic and pharmacodynamic characteristics which allowed for in vivo evaluation in efficacy models. Moreover, the high selectivity of evobrutinib for BTK over epidermal growth factor receptor and other Tec family kinases suggested a low potential for off-target related adverse effects. Clin. investigation of evobrutinib is ongoing in several autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus.
- 38Evans, E. K.; Tester, R.; Aslanian, S.; Karp, R.; Sheets, M.; Labenski, M. T.; Witowski, S. R.; Lounsbury, H.; Chaturvedi, P.; Mazdiyasni, H.; Zhu, Z.; Nacht, M.; Freed, M. I.; Petter, R. C.; Dubrovskiy, A.; Singh, J.; Westlin, W. F. Inhibition of btk with cc-292 provides early pharmacodynamic assessment of activity in mice and humans. J. Pharmacol. Exp. Ther. 2013, 346, 219– 228, DOI: 10.1124/jpet.113.203489[Crossref], [PubMed], [CAS], Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFOjsbbM&md5=95fac997a246e59d943dd554af358a65Inhibition of Btk with CC-292 provides early pharmacodynamic assessment of activity in mice and humansEvans, Erica K.; Tester, Richland; Aslanian, Sharon; Karp, Russell; Sheets, Michael; Labenski, Matthew T.; Witowski, Steven R.; Lounsbury, Heather; Chaturvedi, Prasoon; Mazdiyasni, Hormoz; Zhu, Zhendong; Nacht, Mariana; Freed, Martin I.; Petter, Russell C.; Dubrovskiy, Alex; Singh, Juswinder; Westlin, William F.Journal of Pharmacology and Experimental Therapeutics (2013), 346 (2), 219-228CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)Targeted therapies that suppress B cell receptor (BCR) signaling have emerged as promising agents in autoimmune disease and B cell malignancies. Bruton's tyrosine kinase (Btk) plays a crucial role in B cell development and activation through the BCR signaling pathway and represents a new target for diseases characterized by inappropriate B cell activity. N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide (CC-292) is a highly selective, covalent Btk inhibitor and a sensitive and quant. assay that measures CC-292-Btk engagement has been developed. This translational pharmacodynamic assay has accompanied CC-292 through each step of drug discovery and development. These studies demonstrate the quantity of Btk bound by CC-292 correlates with the efficacy of CC-292 in vitro and in the collagen-induced arthritis model of autoimmune disease. Recently, CC-292 has entered human clin. trials with a trial design that has provided rapid insight into safety, pharmacokinetics, and pharmacodynamics. This first-in-human healthy volunteer trial has demonstrated that a single oral dose of 2 mg/kg CC-292 consistently engaged all circulating Btk protein and provides the basis for rational dose selection in future clin. trials. This targeted covalent drug design approach has enabled the discovery and early clin. development of CC-292 and has provided support for Btk as a valuable drug target for B-cell mediated disorders.
- 39Walter, H. S.; Rule, S. A.; Dyer, M. J.; Karlin, L.; Jones, C.; Cazin, B.; Quittet, P.; Shah, N.; Hutchinson, C. V.; Honda, H.; Duffy, K.; Birkett, J.; Jamieson, V.; Courtenay-Luck, N.; Yoshizawa, T.; Sharpe, J.; Ohno, T.; Abe, S.; Nishimura, A.; Cartron, G.; Morschhauser, F.; Fegan, C.; Salles, G. A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies. Blood 2016, 127, 411– 419, DOI: 10.1182/blood-2015-08-664086[Crossref], [PubMed], [CAS], Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1Cis7zO&md5=f12cd01520c82ddd2067f2b329bd38a9A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignanciesWalter, Harriet S.; Rule, Simon A.; Dyer, Martin J. S.; Karlin, Lionel; Jones, Ceri; Cazin, Bruno; Quittet, Philippe; Shah, Nimish; Hutchinson, Claire V.; Honda, Hideyuki; Duffy, Kevin; Birkett, Joseph; Jamieson, Virginia; Courtenay-Luck, Nigel; Yoshizawa, Toshio; Sharpe, John; Ohno, Tomoya; Abe, Shinichiro; Nishimura, Akihisa; Cartron, Guillaume; Morschhauser, Franck; Fegan, Christopher; Salles, GillesBlood (2016), 127 (4), 411-419CODEN: BLOOAW; ISSN:1528-0020. (American Society of Hematology)We report the results of a multicenter phase 1 dose-escalation study of the selective Bruton tyrosine kinase (BTK) inhibitor ONO/GS-4059 in 90 patients with relapsed/refractory B-cell malignancies. There were 9 dose-escalation cohorts ranging from 20 mg to 600 mg once daily with twice-daily regimens of 240 mg and 300 mg. Twenty-four of 25 evaluable chronic lymphocytic leukemia (CLL) patients (96%) responded to ONO/GS-4059, with a median treatment duration of 80 wk; 21 CLL patients remain on treatment. Lymph node responses were rapid and assocd. with a concurrent lymphocytosis. Eleven of 12 evaluable patients with mantle cell lymphoma (92%) responded (median treatment duration, 40 wk). Eleven of 31 non-germinal center B-cell diffuse large B-cell lymphoma patients (35%) responded but median treatment duration was 12 wk due to development of progressive disease. ONO/GS-4059 was very well tolerated with 75% of adverse events (AEs) being Common Toxicity Criteria for Adverse Events version 4.0 grade 1 or grade 2. Grade 3/4 AEs were mainly hematol. and recovered spontaneously during therapy. One CLL patient experienced a grade 3 treatment-related bleeding event (spontaneous muscle hematoma) but no clin. significant diarrhea, cardiac dysrhythmias, or arthralgia were obsd. No maximal tolerated dose (MTD) was reached in the CLL cohort. In the non-Hodgkin lymphoma cohort, 4 patients developed a dose-limiting toxicity, yielding an MTD of 480 mg once daily. ONO/GS-4059 has significant activity in relapsed/refractory B-cell malignancies without major drug-related toxicity. The selectivity of ONO/GS-4059 should confer advantages in combination therapies.
- 40Watterson, S. H.; Liu, Q.; Beaudoin Bertrand, M.; Batt, D. G.; Li, L.; Pattoli, M. A.; Skala, S.; Cheng, L.; Obermeier, M. T.; Moore, R.; Yang, Z.; Vickery, R.; Elzinga, P. A.; Discenza, L.; D’Arienzo, C.; Gillooly, K. M.; Taylor, T. L.; Pulicicchio, C.; Zhang, Y.; Heimrich, E.; McIntyre, K. W.; Ruan, Q.; Westhouse, R. A.; Catlett, I. M.; Zheng, N.; Chaudhry, C.; Dai, J.; Galella, M. A.; Tebben, A. J.; Pokross, M.; Li, J.; Zhao, R.; Smith, D.; Rampulla, R.; Allentoff, A.; Wallace, M. A.; Mathur, A.; Salter-Cid, L.; Macor, J. E.; Carter, P. H.; Fura, A.; Burke, J. R.; Tino, J. A. Discovery of branebrutinib (BMS-986195): a strategy for identifying a highly potent and selective covalent inhibitor providing rapid in vivo inactivation of Bruton’s tyrosine kinase (BTK). J. Med. Chem. 2019, 62, 3228– 3250, DOI: 10.1021/acs.jmedchem.9b00167[ACS Full Text], [CAS], Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXls1aks7w%253D&md5=2d521ec7c06d503f940cb44d381af58dDiscovery of Branebrutinib (BMS-986195): A Strategy for Identifying a Highly Potent and Selective Covalent Inhibitor Providing Rapid in Vivo Inactivation of Bruton's Tyrosine Kinase (BTK)Watterson, Scott H.; Liu, Qingjie; Beaudoin Bertrand, Myra; Batt, Douglas G.; Li, Ling; Pattoli, Mark A.; Skala, Stacey; Cheng, Lihong; Obermeier, Mary T.; Moore, Robin; Yang, Zheng; Vickery, Rodney; Elzinga, Paul A.; Discenza, Lorell; D'Arienzo, Celia; Gillooly, Kathleen M.; Taylor, Tracy L.; Pulicicchio, Claudine; Zhang, Yifan; Heimrich, Elizabeth; McIntyre, Kim W.; Ruan, Qian; Westhouse, Richard A.; Catlett, Ian M.; Zheng, Naiyu; Chaudhry, Charu; Dai, Jun; Galella, Michael A.; Tebben, Andrew J.; Pokross, Matt; Li, Jianqing; Zhao, Rulin; Smith, Daniel; Rampulla, Richard; Allentoff, Alban; Wallace, Michael A.; Mathur, Arvind; Salter-Cid, Luisa; Macor, John E.; Carter, Percy H.; Fura, Aberra; Burke, James R.; Tino, Joseph A.Journal of Medicinal Chemistry (2019), 62 (7), 3228-3250CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a crit. role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fcε receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacol. inhibition of BTK is anticipated to provide an effective strategy for the clin. treatment of autoimmune diseases such as rheumatoid arthritis and lupus. This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clin. studies.
- 41Angst, D.; Gessier, F.; Janser, P.; Vulpetti, A.; Walchli, R.; Beerli, C.; Littlewood-Evans, A.; Dawson, J.; Nuesslein-Hildesheim, B.; Wieczorek, G.; Gutmann, S.; Scheufler, C.; Hinniger, A.; Zimmerlin, A.; Funhoff, E. G.; Pulz, R.; Cenni, B. Discovery of LOU064 (Remibrutinib), a potent and highly selective covalent inhibitor of Bruton’s tyrosine kinase. J. Med. Chem. 2020, 63, 5102– 5118, DOI: 10.1021/acs.jmedchem.9b01916[ACS Full Text], [CAS], Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXjs1KiurY%253D&md5=9122b310c294d6071ae7cd73cdb91b3dDiscovery of LOU064 (Remibrutinib), a Potent and Highly Selective Covalent Inhibitor of Bruton's Tyrosine KinaseAngst, Daniela; Gessier, Francois; Janser, Philipp; Vulpetti, Anna; Walchli, Rudolf; Beerli, Christian; Littlewood-Evans, Amanda; Dawson, Janet; Nuesslein-Hildesheim, Barbara; Wieczorek, Grazyna; Gutmann, Sascha; Scheufler, Clemens; Hinniger, Alexandra; Zimmerlin, Alfred; Funhoff, Enrico G.; Pulz, Robert; Cenni, BrunoJournal of Medicinal Chemistry (2020), 63 (10), 5102-5118CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Bruton's tyrosine kinase (BTK), a cytoplasmic tyrosine kinase, plays a central role in immunity and is considered an attractive target for treating autoimmune diseases. The use of currently marketed covalent BTK inhibitors is limited to oncol. indications based on their suboptimal kinase selectivity. We describe the discovery and preclin. profile of LOU064 (remibrutinib, 25), a potent, highly selective covalent BTK inhibitor. LOU064 exhibits an exquisite kinase selectivity due to binding to an inactive conformation of BTK and has the potential for a best-in-class covalent BTK inhibitor for the treatment of autoimmune diseases. It demonstrates potent in vivo target occupancy with an EC90 of 1.6 mg/kg and dose-dependent efficacy in rat collagen-induced arthritis. LOU064 is currently being tested in phase 2 clin. studies for chronic spontaneous urticaria and Sjoegren's syndrome.
- 42Crawford, J. J.; Johnson, A. R.; Misner, D. L.; Belmont, L. D.; Castanedo, G.; Choy, R.; Coraggio, M.; Dong, L.; Eigenbrot, C.; Erickson, R.; Ghilardi, N.; Hau, J.; Katewa, A.; Kohli, P. B.; Lee, W.; Lubach, J. W.; McKenzie, B. S.; Ortwine, D. F.; Schutt, L.; Tay, S.; Wei, B.; Reif, K.; Liu, L.; Wong, H.; Young, W. B. Discovery of GDC-0853: a potent, selective, and noncovalent Bruton’s tyrosine kinase inhibitor in early clinical development. J. Med. Chem. 2018, 61, 2227– 2245, DOI: 10.1021/acs.jmedchem.7b01712[ACS Full Text], [CAS], Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXivFCnt7c%253D&md5=eddbd31f387fe86827a7469e8be45430Discovery of GDC-0853: A Potent, Selective, and Noncovalent Bruton's Tyrosine Kinase Inhibitor in Early Clinical DevelopmentCrawford, James J.; Johnson, Adam R.; Misner, Dinah L.; Belmont, Lisa D.; Castanedo, Georgette; Choy, Regina; Coraggio, Melis; Dong, Liming; Eigenbrot, Charles; Erickson, Rebecca; Ghilardi, Nico; Hau, Jonathan; Katewa, Arna; Kohli, Pawan Bir; Lee, Wendy; Lubach, Joseph W.; McKenzie, Brent S.; Ortwine, Daniel F.; Schutt, Leah; Tay, Suzanne; Wei, BinQing; Reif, Karin; Liu, Lichuan; Wong, Harvey; Young, Wendy B.Journal of Medicinal Chemistry (2018), 61 (6), 2227-2245CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Bruton's tyrosine kinase (Btk) is a nonreceptor cytoplasmic tyrosine kinase involved in B-cell and myeloid cell activation, downstream of B-cell and Fcγ receptors, resp. Preclin. studies have indicated that inhibition of Btk activity might offer a potential therapy in autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. Here we disclose the discovery and preclin. characterization of a potent, selective, and noncovalent Btk inhibitor currently in clin. development. GDC-0853 (29) suppresses B cell- and myeloid cell-mediated components of disease and demonstrates dose-dependent activity in an in vivo rat model of inflammatory arthritis. It demonstrates highly favorable safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles in preclin. and Phase 2 studies ongoing in patients with rheumatoid arthritis, lupus, and chronic spontaneous urticaria. On the basis of its potency, selectivity, long target residence time, and noncovalent mode of inhibition, 29 has the potential to be a best-in-class Btk inhibitor for a wide range of immunol. indications.
- 43Young, W. B.; Barbosa, J.; Blomgren, P.; Bremer, M. C.; Crawford, J. J.; Dambach, D.; Gallion, S.; Hymowitz, S. G.; Kropf, J. E.; Lee, S. H.; Liu, L.; Lubach, J. W.; Macaluso, J.; Maciejewski, P.; Maurer, B.; Mitchell, S. A.; Ortwine, D. F.; Di Paolo, J.; Reif, K.; Scheerens, H.; Schmitt, A.; Sowell, C. G.; Wang, X.; Wong, H.; Xiong, J. M.; Xu, J.; Zhao, Z.; Currie, K. S. Potent and selective Bruton’s tyrosine kinase inhibitors: discovery of GDC-0834. Bioorg. Med. Chem. Lett. 2015, 25, 1333– 1337, DOI: 10.1016/j.bmcl.2015.01.032[Crossref], [PubMed], [CAS], Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXisVSit7w%253D&md5=fdebc0199c8222e093cfb9583244bce3Potent and selective Bruton's tyrosine kinase inhibitors: Discovery of GDC-0834Young, Wendy B.; Barbosa, James; Blomgren, Peter; Bremer, Meire C.; Crawford, James J.; Dambach, Donna; Gallion, Steve; Hymowitz, Sarah G.; Kropf, Jeffrey E.; Lee, Seung H.; Liu, Lichuan; Lubach, Joseph W.; Macaluso, Jen; Maciejewski, Pat; Maurer, Brigitte; Mitchell, Scott A.; Ortwine, Daniel F.; Di Paolo, Julie; Reif, Karin; Scheerens, Heleen; Schmitt, Aaron; Sowell, C. Gregory; Wang, Xiaojing; Wong, Harvey; Xiong, Jin-Ming; Xu, Jianjun; Zhao, Zhongdong; Currie, Kevin S.Bioorganic & Medicinal Chemistry Letters (2015), 25 (6), 1333-1337CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)SAR studies focused on improving the pharmacokinetic (PK) properties of the previously reported potent and selective Btk inhibitor CGI-1746 resulted in the clin. candidate GDC-0834, which retained the potency and selectivity of CGI-1746, but with much improved PK in preclin. animal models. Structure based design efforts drove this work as modifications to CGI-1746 were investigated at both the solvent exposed region as well as 'H3 binding pocket'. However, in vitro metabolic evaluation of GDC-0834 revealed a non CYP-mediated metabolic process that was more prevalent in human than preclin. species (mouse, rat, dog, cyno), leading to a high-level of uncertainly in predicting human pharmacokinetics. Due to its promising potency, selectivity, and preclin. efficacy, a single dose IND was filed and GDC-0834 was taken in to a single dose phase I trial in healthy volunteers to quickly evaluate the human pharmacokinetics. In human, GDC-0834 was found to be highly labile at the exo-cyclic amide bond that links the tetrahydrobenzothiophene moiety to the central aniline ring, resulting in insufficient parent drug exposure. This information informed the back-up program and discovery of improved inhibitors.
- 44Herman, A. E.; Chinn, L. W.; Kotwal, S. G.; Murray, E. R.; Zhao, R.; Florero, M.; Lin, A.; Moein, A.; Wang, R.; Bremer, M.; Kokubu, S.; Serone, A. P.; Hanze, E. L.; Viberg, A.; Morimoto, A. M.; Winter, H. R.; Katsumoto, T. R. Safety, pharmacokinetics, and pharmacodynamics in healthy volunteers treated with GDC-0853, a selective reversible Bruton’s tyrosine kinase inhibitor. Clin. Pharmacol. Ther. 2018, 103, 1020– 1028, DOI: 10.1002/cpt.1056[Crossref], [PubMed], [CAS], Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVOqsrrK&md5=5384437ef44533ca18cd8f768ad853f3Safety, Pharmacokinetics, and Pharmacodynamics in Healthy Volunteers Treated With GDC-0853, a Selective Reversible Bruton's Tyrosine Kinase InhibitorHerman, Ann E.; Chinn, Leslie W.; Kotwal, Shweta G.; Murray, Elaine R.; Zhao, Rui; Florero, Marilyn; Lin, Alyse; Moein, Anita; Wang, Rena; Bremer, Meire; Kokubu, Serika; Serone, Adrian P.; Hanze, Eva L.; Viberg, Anders; Morimoto, Alyssa M.; Winter, Helen R.; Katsumoto, Tamiko R.Clinical Pharmacology & Therapeutics (Hoboken, NJ, United States) (2018), 103 (6), 1020-1028CODEN: CLPTAT; ISSN:0009-9236. (John Wiley & Sons, Inc.)GDC-0853 is a small mol. inhibitor of Bruton's tyrosine kinase (BTK) that is highly selective and noncovalent, leading to reversible binding. In double-blind, randomized, and placebo-controlled phase I healthy volunteer studies, GDC-0853 was well tolerated, with no dose-limiting adverse events (AEs) or serious AEs. The max. tolerated dose was not reached during dose escalation (≤ 600 mg, single ascending dose (SAD) study; ≤ 250 mg twice daily (b.i.d.) and ≤ 500 mg once daily, 14-day multiple ascending dose (MAD) study). Plasma concns. peaked 1-3 h after oral administration and declined thereafter, with a steady-state half-life ranging from 4.2-9.9 h. Independent assays demonstrated dose-dependent BTK target engagement. Based on pharmacokinetic/pharmacodynamic (PK/PD) simulations, a once-daily dosing regimen (e.g., 100 mg, q.d.) is expected to maintain a high level of BTK inhibition over the dosing interval. Taken together, the safety and PK/PD data support GDC-0853 evaluation in rheumatoid arthritis, lupus, and other autoimmune or inflammatory indications.
- 45Byrd, J. C.; Smith, S.; Wagner-Johnston, N.; Sharman, J.; Chen, A. I.; Advani, R.; Augustson, B.; Marlton, P.; Renee Commerford, S.; Okrah, K.; Liu, L.; Murray, E.; Penuel, E.; Ward, A. F.; Flinn, I. W. First-in-human phase 1 study of the BTK inhibitor GDC-0853 in relapsed or refractory B-cell NHL and CLL. Oncotarget 2018, 9, 13023– 13035, DOI: 10.18632/oncotarget.24310[Crossref], [PubMed], [CAS], Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1Mnjt1Srug%253D%253D&md5=6fa90aae6c292025323e7eef768e93cfFirst-in-human phase 1 study of the BTK inhibitor GDC-0853 in relapsed or refractory B-cell NHL and CLLByrd John C; Smith Stephen; Wagner-Johnston Nina; Sharman Jeff; Chen Andy I; Advani Ranjana; Augustson Bradley; Marlton Paula; Renee Commerford S; Okrah Kwame; Liu Lichuan; Murray Elaine; Penuel Elicia; Ward Ashley F; Flinn Ian WOncotarget (2018), 9 (16), 13023-13035 ISSN:.GDC-0853 is a selective, reversible, and non-covalent inhibitor of Bruton's tyrosine kinase (BTK) that does not require interaction with the Cys481 residue for activity. In this first-in-human phase 1 study we evaluated safety, tolerability, pharmacokinetics, and activity of GDC-0853 in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL). Twenty-four patients, enrolled into 3 cohorts, including 6 patients who were positive for the C481S mutation, received GDC-0853 at 100, 200, or 400 mg once daily, orally. There were no dose limiting toxicities. GDC-0853 was well tolerated and the maximum tolerated dose (MTD) was not reached due to premature study closure. Common adverse events (AEs) in ≥ 15% of patients regardless of causality included fatigue (37%), nausea (33%), diarrhea (29%), thrombocytopenia (25%), headache (20%), and abdominal pain, cough, and dizziness (16%, each). Nine serious AEs were reported in 5 patients of whom 2 had fatal outcomes (confirmed H1N1 influenza and influenza pneumonia). A third death was due to progressive disease. Eight of 24 patients responded to GDC-0853: 1 complete response, 4 partial responses, and 3 partial responses with lymphocytosis, including 1 patient with the C481S mutation. Two additional C481S mutation patients had a decrease in size of target tumors (-23% and -44%). These data demonstrate GDC-0853 was generally well-tolerated with antitumor activity.
- 46Watterson, S. H.; De Lucca, G. V.; Shi, Q.; Langevine, C. M.; Liu, Q.; Batt, D. G.; Beaudoin Bertrand, M.; Gong, H.; Dai, J.; Yip, S.; Li, P.; Sun, D.; Wu, D.-R.; Wang, C.; Zhang, Y.; Traeger, S. C.; Pattoli, M. A.; Skala, S.; Cheng, L.; Obermeier, M. T.; Vickery, R.; Discenza, L. N.; D’Arienzo, C. J.; Zhang, Y.; Heimrich, E.; Gillooly, K. M.; Taylor, T. L.; Pulicicchio, C.; McIntyre, K. W.; Galella, M. A.; Tebben, A. J.; Muckelbauer, J. K.; Chang, C.; Rampulla, R.; Mathur, A.; Salter-Cid, L.; Barrish, J. C.; Carter, P. H.; Fura, A.; Burke, J. R.; Tino, J. A. Discovery of 6-fluoro-5-(r)-(3-(s)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4h)-yl)-2-methylphenyl)-2-(s)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8- carboxamide (BMS-986142): a reversible inhibitor of Bruton’s tyrosine kinase (BTK) conformationally constrained by two locked atropisomers. J. Med. Chem. 2016, 59, 9173– 9200, DOI: 10.1021/acs.jmedchem.6b01088[ACS Full Text], [CAS], Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVKjsrfF&md5=91098abc802521b9ad91563d20ac5893Discovery of 6-Fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (BMS-986142): A Reversible Inhibitor of Bruton's Tyrosine Kinase (BTK) Conformationally Constrained by Two Locked AtropisomersWatterson, Scott H.; De Lucca, George V.; Shi, Qing; Langevine, Charles M.; Liu, Qingjie; Batt, Douglas G.; Beaudoin Bertrand, Myra; Gong, Hua; Dai, Jun; Yip, Shiuhang; Li, Peng; Sun, Dawn; Wu, Dauh-Rurng; Wang, Chunlei; Zhang, Yingru; Traeger, Sarah C.; Pattoli, Mark A.; Skala, Stacey; Cheng, Lihong; Obermeier, Mary T.; Vickery, Rodney; Discenza, Lorell N.; D'Arienzo, Celia J.; Zhang, Yifan; Heimrich, Elizabeth; Gillooly, Kathleen M.; Taylor, Tracy L.; Pulicicchio, Claudine; McIntyre, Kim W.; Galella, Michael A.; Tebben, Andy J.; Muckelbauer, Jodi K.; Chang, ChiehYing; Rampulla, Richard; Mathur, Arvind; Salter-Cid, Luisa; Barrish, Joel C.; Carter, Percy H.; Fura, Aberra; Burke, James R.; Tino, Joseph A.Journal of Medicinal Chemistry (2016), 59 (19), 9173-9200CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcγ receptor signaling in monocytes and Fcε receptor signaling in mast cells and basophils, all of which have been implicated in the pathophysiol. of autoimmune disease. As a result, inhibition of BTK is anticipated to provide an effective strategy for the clin. treatment of autoimmune diseases such as lupus and rheumatoid arthritis. This article details the structure-activity relationships (SAR) leading to a novel series of highly potent and selective carbazole and tetrahydrocarbazole based, reversible inhibitors of BTK. Of particular interest is that two atropisomeric centers were rotationally locked to provide a single, stable atropisomer, resulting in enhanced potency and selectivity as well as a redn. in safety liabilities. With significantly enhanced potency and selectivity, excellent in vivo properties and efficacy, and a very desirable tolerability and safety profile, 14f (BMS-986142) was advanced into clin. studies.
- 47Lee, S. K.; Xing, J.; Catlett, I. M.; Adamczyk, R.; Griffies, A.; Liu, A.; Murthy, B.; Nowak, M. Safety, pharmacokinetics, and pharmacodynamics of BMS-986142, a novel reversible BTK inhibitor, in healthy participants. Eur. J. Clin. Pharmacol. 2017, 73, 689– 698, DOI: 10.1007/s00228-017-2226-2[Crossref], [PubMed], [CAS], Google Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjvVahs70%253D&md5=d1435ec2479d5a50d0a5b863cc98d803Safety, pharmacokinetics, and pharmacodynamics of BMS-986142, a novel reversible BTK inhibitor, in healthy participantsLee, Sun Ku; Xing, Jun; Catlett, Ian M.; Adamczyk, Robert; Griffies, Amber; Liu, Ang; Murthy, Bindu; Nowak, MiroslawaEuropean Journal of Clinical Pharmacology (2017), 73 (6), 689-698CODEN: EJCPAS; ISSN:0031-6970. (Springer)BMS-986142 is an oral, small-mol. reversible inhibitor of Bruton's tyrosine kinase. The main objectives of our phase I studies were to characterize the safety and tolerability, pharmacokinetics, and pharmacodynamics of BMS-986142 in healthy participants, and to investigate the potential for the effect of BMS-986142 on the PK of methotrexate (MTX) in combination. In a combined single ascending dose and multiple ascending dose study, the safety, pharmacokinetics, and pharmacodynamics of BMS-986142 were assessed in healthy non-Japanese participants following administration of a single dose (5-900 mg) or multiple doses (25-350 mg, once daily for 14 days). In a drug-drug interaction study, the effect of BMS-986142 (350 mg, once daily for 5 days) on the single-dose pharmacokinetics of MTX (7.5 mg) was assessed in healthy participants. Results: BMS-986142 was generally well tolerated, alone and in combination with MTX. BMS-986142 was rapidly absorbed with peak concns. occurring within 2 h, and was eliminated with a mean half-life ranging from 7 to 11 h. Exposure of BMS-986142 appeared dose proportional within the dose ranges tested. A dose- and concn.-dependent inhibition of CD69 expression was obsd. following administration of BMS-986142. BMS-986142 did not affect the pharmacokinetics of MTX. BMS-986142 was well tolerated at the doses tested, had pharmacokinetic and pharmacodynamic profiles which support once-daily dosing, and can be coadministered with MTX without the pharmacokinetic interaction of BMS-986142 on MTX.
- 48Lou, Y.; Han, X.; Kuglstatter, A.; Kondru, R. K.; Sweeney, Z. K.; Soth, M.; McIntosh, J.; Litman, R.; Suh, J.; Kocer, B.; Davis, D.; Park, J.; Frauchiger, S.; Dewdney, N.; Zecic, H.; Taygerly, J. P.; Sarma, K.; Hong, J.; Hill, R. J.; Gabriel, T.; Goldstein, D. M.; Owens, T. D. Structure-based drug design of RN486, a potent and selective Bruton’s tyrosine kinase (BTK) inhibitor, for the treatment of rheumatoid arthritis. J. Med. Chem. 2015, 58, 512– 516, DOI: 10.1021/jm500305p[ACS Full Text], [CAS], Google Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXlsl2qtb8%253D&md5=dc3c069b0e876f44846a30e3aa6a894aStructure-Based Drug Design of RN486, a Potent and Selective Bruton's Tyrosine Kinase (BTK) Inhibitor, for the Treatment of Rheumatoid ArthritisLou, Yan; Han, Xiaochun; Kuglstatter, Andreas; Kondru, Rama K.; Sweeney, Zachary K.; Soth, Michael; McIntosh, Joel; Litman, Renee; Suh, Judy; Kocer, Buelent; Davis, Dana; Park, Jaehyeon; Frauchiger, Sandra; Dewdney, Nolan; Zecic, Hasim; Taygerly, Joshua P.; Sarma, Keshab; Hong, Junbae; Hill, Ronald J.; Gabriel, Tobias; Goldstein, David M.; Owens, Timothy D.Journal of Medicinal Chemistry (2015), 58 (1), 512-516CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alc. group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compd. I (RN486) (J. Pharmacol. Exp. Ther. 2012, 341, 90), which was selected for advanced preclin. characterization based on its favorable properties.
- 49Smith, C. R.; Dougan, D. R.; Komandla, M.; Kanouni, T.; Knight, B.; Lawson, J. D.; Sabat, M.; Taylor, E. R.; Vu, P.; Wyrick, C. Fragment-based discovery of a small molecule inhibitor of Bruton’s tyrosine kinase. J. Med. Chem. 2015, 58, 5437– 5444, DOI: 10.1021/acs.jmedchem.5b00734[ACS Full Text], [CAS], Google Scholar49https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVans7rF&md5=d6626fabcc3e2aa6a9180dc702a5030cFragment-Based Discovery of a Small Molecule Inhibitor of Bruton's Tyrosine KinaseSmith, Christopher R.; Dougan, Douglas R.; Komandla, Mallareddy; Kanouni, Toufike; Knight, Beverly; Lawson, J. David; Sabat, Mark; Taylor, Ewan R.; Vu, Phong; Wyrick, CoreyJournal of Medicinal Chemistry (2015), 58 (14), 5437-5444CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The discovery and optimization of a series of 4-aminocinnoline-3-carboxamide inhibitors of Bruton's tyrosine kinase are reported. A fragment-based screening approach incorporating x-ray cocrystallog. was used to identify a cinnoline fragment and characterize its binding mode in the ATP binding site of Btk. Optimization of the fragment hit resulted in the identification of a lead compd. I which reduced paw swelling in a dose- and exposure-dependent fashion in a rat model of collagen-induced arthritis.
- 50Kawahata, W.; Asami, T.; Kiyoi, T.; Irie, T.; Taniguchi, H.; Asamitsu, Y.; Inoue, T.; Miyake, T.; Sawa, M. Design and synthesis of novel amino-triazine analogues as selective Bruton’s tyrosine kinase inhibitors for treatment of rheumatoid arthritis. J. Med. Chem. 2018, 61, 8917– 8933, DOI: 10.1021/acs.jmedchem.8b01147[ACS Full Text], [CAS], Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslaitLbK&md5=56afc013f74a2912624c57c61a197845Design and Synthesis of Novel Amino-triazine Analogues as Selective Bruton's Tyrosine Kinase Inhibitors for Treatment of Rheumatoid ArthritisKawahata, Wataru; Asami, Tokiko; Kiyoi, Takao; Irie, Takayuki; Taniguchi, Haruka; Asamitsu, Yuko; Inoue, Tomoko; Miyake, Takahiro; Sawa, MasaakiJournal of Medicinal Chemistry (2018), 61 (19), 8917-8933CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Bruton's tyrosine kinase (BTK) is a promising drug target for the treatment of multiple diseases, such as B-cell malignances, asthma, and rheumatoid arthritis. A series of novel aminotriazines were identified as highly selective inhibitors of BTK by a scaffold-hopping approach. Subsequent SAR studies of this series using two conformationally different BTK proteins, an activated form of BTK and an unactivated form of BTK, led to the discovery of a highly selective BTK inhibitor, I. With significant efficacy in models in vivo and good ADME and safety profiles, I was advanced into preclin. studies.
- 51Yao, X.; Sun, X.; Jin, S.; Yang, L.; Xu, H.; Rao, Y. Discovery of 4-aminoquinoline-3-carboxamide derivatives as potent reversible Bruton’s tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. J. Med. Chem. 2019, 62, 6561– 6574, DOI: 10.1021/acs.jmedchem.9b00329[ACS Full Text], [CAS], Google Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtlamsrvF&md5=1eca629234ee9e3b95e1497526851e2aDiscovery of 4-Aminoquinoline-3-carboxamide Derivatives as Potent Reversible Bruton's Tyrosine Kinase Inhibitors for the Treatment of Rheumatoid ArthritisYao, Xia; Sun, Xiuyun; Jin, Shuyu; Yang, Ling; Xu, Hongjiang; Rao, YuJournal of Medicinal Chemistry (2019), 62 (14), 6561-6574CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A structure-hopping strategy was applied to discover a series of novel 4-aminoquinoline-3-carboxamide derivs. as potent, reversible BTK inhibitors. Compared to the previously described cinnoline scaffold compds., the 4-aminoquinoline analogs showed significantly improved drug-like properties, esp. in their aq. soly. The most potent compd., 25, displayed a stronger inhibitory effect on both BTKWT (IC50 = 5.3 nM) and BTKC481S (IC50 = 39 nM). In a rodent collagen-induced arthritis model, compd. 25 efficiently reduced paw swelling without a loss in body wt. On the basis of potency, drug-like properties, stability, and noncovalent mode of inhibition, our representative inhibitors could have a promising profile to be treatments for a wide range of autoimmune diseases.
- 52Amano, M.; Nakayama, M.; Kaibuchi, K. Rho-kinase/ROCK: A key regulator of the cytoskeleton and cell polarity. Cytoskeleton 2010, 67, 545– 554, DOI: 10.1002/cm.20472[Crossref], [CAS], Google Scholar52https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFOrs7vM&md5=fa704bca66855ebd20461a3410580ed4Rho-kinase/ROCK: a key regulator of the cytoskeleton and cell polarityAmano, Mutsuki; Nakayama, Masanori; Kaibuchi, KozoCytoskeleton (2010), 67 (9), 545-554CODEN: CYTOBO; ISSN:1949-3584. (Wiley-Blackwell)A review. Rho-assocd. kinase (Rho-kinase/ROCK/ROK) is an effector of the small GTPase Rho and belongs to the AGC family of kinases. Rho-kinase has pleiotropic functions including the regulation of cellular contraction, motility, morphol., polarity, cell division, and gene expression. Pharmacol. analyses have revealed that Rho-kinase is involved in a wide range of diseases such as vasospasm, pulmonary hypertension, nerve injury, and glaucoma, and is therefore considered to be a potential therapeutic target. This review focuses on the structure, function, and modes of activation and action of Rho-kinase.
- 53Feng, Y. B.; LoGrasso, P. V.; Defert, O.; Li, R. S. Rho kinase (ROCK) inhibitors and their therapeutic potential. J. Med. Chem. 2016, 59, 2269– 2300, DOI: 10.1021/acs.jmedchem.5b00683[ACS Full Text], [CAS], Google Scholar53https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1Oqtb%252FJ&md5=99b0e10dca303023b1bf382fcb255771Rho Kinase (ROCK) Inhibitors and Their Therapeutic PotentialFeng, Yangbo; LoGrasso, Philip V.; Defert, Olivier; Li, RongshiJournal of Medicinal Chemistry (2016), 59 (6), 2269-2300CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Rho kinases (ROCKs) belong to the serine-threonine family, the inhibition of which affects the function of many downstream substrates. As such, ROCK inhibitors have potential therapeutic applicability in a wide variety of pathol. conditions including asthma, cancer, erectile dysfunction, glaucoma, insulin resistance, kidney failure, neuronal degeneration, and osteoporosis. To date, two ROCK inhibitors have been approved for clin. use in Japan (fasudil and ripasudil) and one in China (fasudil). In 1995 fasudil was approved for the treatment of cerebral vasospasm, and more recently, ripasudil was approved for the treatment of glaucoma in 2014. In this Perspective, we present a comprehensive review of the physiol. and biol. functions for ROCK, the properties and development of over 170 ROCK inhibitors as well as their therapeutic potential, the current status, and future considerations.
- 54Nourinia, R.; Nakao, S.; Zandi, S.; Safi, S.; Hafezi-Moghadam, A.; Ahmadieh, H. ROCK inhibitors for the treatment of ocular diseases. Br. J. Ophthalmol. 2018, 102, 1– 5, DOI: 10.1136/bjophthalmol-2017-310378
- 55Lin, C. W.; Sherman, B.; Moore, L. A.; Laethem, C. L.; Lu, D. W.; Pattabiraman, P. P.; Rao, P. V.; deLong, M. A.; Kopczynski, C. C. Discovery and preclinical development of netarsudil, a novel ocular hypotensive agent for the treatment of glaucoma. J. Ocul. Pharmacol. Ther. 2018, 34, 40– 51, DOI: 10.1089/jop.2017.0023[Crossref], [PubMed], [CAS], Google Scholar55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXivFCns7w%253D&md5=0aab049b2ff35df0ce0f03b33bb5f501Discovery and Preclinical Development of Netarsudil, a Novel Ocular Hypotensive Agent for the Treatment of GlaucomaLin, Cheng-Wen; Sherman, Bryan; Moore, Lori A.; Laethem, Carmen L.; Lu, Da-Wen; Pattabiraman, Padmanabhan P.; Rao, Ponugoti Vasantha; de Long, Mitchell A.; Kopczynski, Casey C.Journal of Ocular Pharmacology and Therapeutics (2018), 34 (1-2), 40-51CODEN: JOPTFU; ISSN:1080-7683. (Mary Ann Liebert, Inc.)Purpose: Rho-assocd. protein kinase (ROCK) inhibitors lower intraocular pressure (IOP) by increasing aq. outflow through the trabecular meshwork (TM). The preclin. characterization of netarsudil, a new ROCK/norepinephrine transporter (NET) inhibitor currently in clin. development, is presented herein. Methods: The kinase inhibitory activity of netarsudil was compared to its esterase metabolite, netarsudil-M1, and 3 other ROCK inhibitors using a com. available kinase assay kit. Disruption of actin stress fibers was measured in primary porcine TM cells and disruption of focal adhesions in transformed human TM (HTM) cells. Induction of fibrosis markers after exposure to transforming growth factor-β2 (TGF-β2) was conducted in primary HTM cells. Ocular hypotensive activity and tolerability of topical formulations were evaluated in normotensive Dutch Belted rabbits and Formosan Rock monkeys. In vitro corneal metab. assays were conducted using dog, pig, rabbit, monkey, and human corneas. In vivo ocular pharmacokinetics was studied in Dutch Belted rabbits. Results: Netarsudil inhibited kinases ROCK1 and ROCK2 with a Ki of 1 nM each, disrupted actin stress fibers and focal adhesions in TM cells with IC50s of 79 and 16 nM, resp., and blocked the profibrotic effects of TGF-β2 in HTM cells. Netarsudil produced large redns. in IOP in rabbits and monkeys that were sustained for at least 24 h after once daily dosing, with transient, mild hyperemia obsd. as the only adverse effect. Conclusion: Netarsudil is a novel ROCK/NET inhibitor with high potency in biochem. and cell-based assays, an ability to produce large and durable IOP redns. in animal models, and favorable pharmacokinetic and ocular tolerability profiles.
- 56Nagumo, H.; Sasaki, Y.; Ono, Y.; Okamoto, H.; Seto, M.; Takuwa, Y. Rho kinase inhibitor HA-1077 prevents Rho-mediated myosin phosphatase inhibition in smooth muscle cells. Am. J. Physiol Cell Physiol 2000, 278, C57– 65, DOI: 10.1152/ajpcell.2000.278.1.C57
- 57Yamaguchi, H.; Kasa, M.; Amano, M.; Kaibuchi, K.; Hakoshima, T. Molecular mechanism for the regulation of rho-kinase by dimerization and its inhibition by fasudil. Structure 2006, 14, 589– 600, DOI: 10.1016/j.str.2005.11.024[Crossref], [PubMed], [CAS], Google Scholar57https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xit1ylt78%253D&md5=c00104ab0fe7731e51b68b3762ee894aMolecular Mechanism for the Regulation of Rho-Kinase by Dimerization and Its Inhibition by FasudilYamaguchi, Hiroto; Kasa, Miyuki; Amano, Mutsuki; Kaibuchi, Kozo; Hakoshima, ToshioStructure (Cambridge, MA, United States) (2006), 14 (3), 589-600CODEN: STRUE6; ISSN:0969-2126. (Cell Press)Rho-kinase is a key regulator of cytoskeletal events and a promising drug target in the treatment of vascular diseases and neurol. disorders. Unlike other protein kinases, Rho-kinase requires both N- and C-terminal extension segments outside the kinase domain for activity, although the details of this requirement have been elusive. The crystal structure of an active Rho-kinase fragment contg. the kinase domain and both the extensions revealed a head-to-head homodimer through the N-terminal extension forming a helix bundle that structurally integrates the C-terminal extension. This structural organization enables binding of the C-terminal hydrophobic motif to the N-terminal lobe, which defines the correct disposition of helix αC that is important for the catalytic activity. The bound inhibitor fasudil significantly alters the conformation and, consequently, the mode of interaction with the catalytic cleft that contains local structural changes. Thus, both kinase and drug conformational pliability and stability confer selectivity.
- 58Raja, S. G. Evaluation of clinical efficacy of fasudil for the treatment of pulmonary arterial hypertension. Recent Pat. Cardiovasc. Drug Discovery 2012, 7, 100– 104, DOI: 10.2174/157489012801227238[Crossref], [PubMed], [CAS], Google Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVOqsLrF&md5=8ffecab28efd9a852eabb916f93b834bEvaluation of clinical efficacy of fasudil for the treatment of pulmonary arterial hypertensionRaja, Shahzad G.Recent Patents on Cardiovascular Drug Discovery (2012), 7 (2), 100-104CODEN: RPCDFC; ISSN:1574-8901. (Bentham Science Publishers Ltd.)A review. Multiple cell types in the vascular wall rely upon the rho-kinase (ROCK) signaling pathway for homeostatic function and response to injury. These cell types include endothelial and vascular smooth muscle cells, inflammatory cells, and fibroblasts. Rho is a guanosine triphosphate binding protein that activates its downstream target rho-kinase, in response to activation of a variety of G-protein coupled receptors. When activated, ROCK inhibits myosin phosphatase and conversely upregulates the ezrin-radixin-moesin family of kinases. In vitro activation of these signaling cascades results in modulation of multiple cellular processes, including enhanced vasoconstriction, proliferation, impaired endothelial response to vasodilators, chronic pulmonary remodeling, and upregulation of vasoactive cytokines via the NF-κB transcription pathway. ROCK activity has also been linked specifically to a no. of known effectors of pulmonary arterial hypertension (PAH), including endothelin-1, serotonin, and endothelial nitric oxide synthase, among others. Recently, elevated ROCK activity has been demonstrated in various animal models of PAH with ROCK inhibitors assocd. with pulmonary vasodilatation and regression of PAH. ROCK inhibitors are a new class of agents which may be beneficial in the treatment of PAH. Fasudil (Daiichi Chem. and Pharmacol. Company, Ibaragi, Japan), a first generation ROCK inhibitor, has been widely studied. Emerging evidence from both animal and human studies suggests that fasudil can promote vasodilation independent of the mechanism that induces vasoconstriction and will be useful in conditions in which endothelial function is impaired including PAH. Several recent patents have described fasudil as a potential therapeutic option in PAH. This article provides an overview of the role of ROCK in the pathogenesis of PAH and discusses the clin. efficacy of fasudil as a therapeutic option for treating PAH.
- 59Garnock-Jones, K. P. Ripasudil: first global approval. Drugs 2014, 74, 2211– 2215, DOI: 10.1007/s40265-014-0333-2[Crossref], [PubMed], [CAS], Google Scholar59https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvF2htrzL&md5=e87121e469a273b2f95f9e4011dfea71Ripasudil: First Global ApprovalGarnock-Jones, Karly P.Drugs (2014), 74 (18), 2211-2215CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)A review. Ripasudil hydrochloride hydrate (Glanatec ophthalmic soln. 0.4 %; hereafter referred to as ripasudil) is a small-mol., Rho-assocd. kinase inhibitor developed by Kowa Company, Ltd. for the treatment of glaucoma and ocular hypertension. This compd., which was originally discovered by D. Western Therapeutics Institute, Inc., reduces intraocular pressure (IOP) by directly acting on the trabecular meshwork, thereby increasing conventional outflow through the Schlemm's canal. As a result of this mechanism of action, ripasudil may offer additive effects in the treatment of glaucoma and ocular hypertension when used in combination with agents such as prostaglandin analogs (which increase uveoscleral outflow) and β blockers (which reduce aq. prodn.). The eye drop product has been approved in Japan for the twice-daily treatment of glaucoma and ocular hypertension, when other therapeutic agents are not effective or cannot be administered. Phase II study is underway for the treatment of diabetic retinopathy. This article summarizes the milestones in the development of ripasudil leading to the first approval for glaucoma and ocular hypertension.
- 60Okumura, N.; Okazaki, Y.; Inoue, R.; Kakutani, K.; Nakano, S.; Kinoshita, S.; Koizumi, N. Effect of the rho-associated kinase inhibitor eye drop (Ripasudil) on corneal endothelial wound healing. Invest. Ophthalmol. Visual Sci. 2016, 57, 1284– 1292, DOI: 10.1167/iovs.15-18586[Crossref], [PubMed], [CAS], Google Scholar60https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XpvVaqur4%253D&md5=51a3e580b0b118d22558bc026a5909b2Effect of the rho-associated kinase inhibitor eye drop (ripasudil) on corneal endothelial wound healingOkumura, Naoki; Okazaki, Yugo; Inoue, Ryota; Kakutani, Kazuya; Nakano, Shinichiro; Kinoshita, Shigeru; Koizumi, NorikoInvestigative Ophthalmology & Visual Science (2016), 57 (3), 1284-1292CODEN: IOVSDA; ISSN:1552-5783. (Association for Research in Vision and Ophthalmology)PURPOSE. Ripasudil (Glanatec), a selective rho-assocd. coiled coil-contg. protein kinase (ROCK) inhibitor, was approved as a glaucoma and ocular hypertension treatment in Japan in 2014. The purpose of this study was to investigate the feasibility of using ripasudil eye drops to treat corneal endothelial injuries. METHODS. Cultured human corneal endothelial cells (HCECs) were treated with ripasudil, and 5-bromo-2'-deoxyuridine (BrdU) incorporation was evaluated by ELISA. A rabbit corneal endothelial damage model was also created by mech. scraping the corneal endothelium, followed by topical ripasudil eye drop application for 2 wk. The anterior segment was evaluated by slit-lamp microscopy, and central corneal thickness was measured by ultrasound pachymetry. Corneal specimens were evaluated by phalloidin staining and immunohistochem. anal. using antibodies against Ki67, N-cadherin, and Na+/K+-ATPase. RESULTS. Many more BrdU-pos. cells were obsd. among the HCECs treated with ripasudil (0.3-30 μM) than among the control HCECs. Ripasudil-treated eyes in a rabbit model showed 91.5 ± 2.0% Ki67-pos. cells after 48 h, whereas control eyes showed 52.6 ± 1.3%. Five of six corneas became transparent in ripasudil-treated eyes, whereas zero of six corneas became transparent in the control eyes. Regenerated cell densities were higher in the eyes treated with ripasudil than in eyes treated with vehicle. Eyes treated with ripasudil expressed N-cadherin and Na+/K+-ATPase in almost all CECs, whereas this expression was decreased in control eyes. CONCLUSIONS. Ripasudil promoted corneal endothelial wound healing, supporting its development as eye drops for treating acute corneal endothelial damage due to eye surgeries, esp. cataract surgery.
- 61Futakuchi, A.; Inoue, T.; Fujimoto, T.; Inoue-Mochita, M.; Kawai, M.; Tanihara, H. The effects of ripasudil (K-115), a Rho kinase inhibitor, on activation of human conjunctival fibroblasts. Exp. Eye Res. 2016, 149, 107– 115, DOI: 10.1016/j.exer.2016.07.001[Crossref], [PubMed], [CAS], Google Scholar61https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFyhtrjP&md5=ab32c0a37390d169f6675c1364e38534The effects of ripasudil (K-115), a Rho kinase inhibitor, on activation of human conjunctival fibroblastsFutakuchi, Akiko; Inoue, Toshihiro; Fujimoto, Tomokazu; Inoue-Mochita, Miyuki; Kawai, Motofumi; Tanihara, HidenobuExperimental Eye Research (2016), 149 (), 107-115CODEN: EXERA6; ISSN:0014-4835. (Elsevier Ltd.)The most common cause of glaucoma surgery failure is scar formation induced by activation of wound-healing responses and resultant fibrosis at the surgical site. We investigated the effects of ripasudil, a Rho kinase inhibitor, on activation of human conjunctival fibroblasts (HConF). HConF were pretreated with different concns. of ripasudil for 1 h before addn. of transforming growth factor (TGF)-β2, followed by incubation for 48 h. TGF-β2-treated fibroblasts exhibited a significant increase in expression of α-smooth muscle actin (α-SMA), a marker of fibroblast-to-myofibroblast differentiation, and this increase was significantly suppressed, in a dose-dependent manner, by pretreatment with ripasudil. Ripasudil pretreatment also significantly attenuated TGF-β2-induced fibronectin prodn. and collagen gel contraction. TGF-β2 increased both the no. of viable cells and the no. of cells in the G2/M phase of the cell cycle; these effects were attenuated by pretreatment with ripasudil. In addn., we explored the effects of ripasudil on stimulation of HConF by activated macrophages. Human monocytic cell line THP-1 cells were differentiated into M1 or M2 macrophage-like cells, and HConF were treated with conditioned media derived from these macrophages in the presence or absence of ripasudil. Conditioned medium from M2 macrophage-like cells induced a significant increase in α-SMA expression, viable cell nos., and gel contraction, all of which were significantly suppressed by ripasudil. Thus, overall, ripasudil attenuated activation of human conjunctival fibroblasts. Ripasudil may be of therapeutic utility, preventing excessive scarring after glaucoma filtration surgery.
- 62Nakata, J.; Akiba, Y.; Nihara, J.; Thant, L.; Eguchi, K.; Kato, H.; Izumi, K.; Ohkura, M.; Otake, M.; Kakihara, Y.; Saito, I.; Saeki, M. ROCK inhibitors enhance bone healing by promoting osteoclastic and osteoblastic differentiation. Biochem. Biophys. Res. Commun. 2020, 526, 547– 552, DOI: 10.1016/j.bbrc.2020.03.033[Crossref], [PubMed], [CAS], Google Scholar62https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXlt1Wls7o%253D&md5=e625e2f9e50d2b4b03c4739a52e54b41ROCK inhibitors enhance bone healing by promoting osteoclastic and osteoblastic differentiationNakata, Juri; Akiba, Yosuke; Nihara, Jun; Thant, Lay; Eguchi, Kaori; Kato, Hiroko; Izumi, Kenji; Ohkura, Mariko; Otake, Masanori; Kakihara, Yoshito; Saito, Isao; Saeki, MakioBiochemical and Biophysical Research Communications (2020), 526 (3), 547-552CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)Osteoclast and osteoblast are essential for proper bone development and remodeling as well as recovery of bone fracture. In this study, we seek chem. compds. that enhance turnover of bone metab. for promoting bone healing. First, we screen a chem. library which includes 378 compds. by using murine pre-osteoclastic RAW264.7 cells to identify compds. that promote osteoclastic differentiation. We find that two ROCK (Rho-assocd. coiled-coil kinase) inhibitors, HA-1077 (Fasudil) and Y-27632, enhance osteoclastogenesis. Subsequently, we identify that these two compds. also increase osteoblastic differentiation of MC3T3-E1 cells. Finally, our in vivo expt. shows that the local administration of ROCK inhibitors accelerate the bone healing of the rat calvarial defect.
- 63Hamano, T.; Shirafuji, N.; Yen, S. H.; Yoshida, H.; Kanaan, N. M.; Hayashi, K.; Ikawa, M.; Yamamura, O.; Fujita, Y.; Kuriyama, M.; Nakamoto, Y. Rho-kinase ROCK inhibitors reduce oligomeric tau protein. Neurobiol. Aging 2020, 89, 41– 54, DOI: 10.1016/j.neurobiolaging.2019.12.009[Crossref], [PubMed], [CAS], Google Scholar63https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXjtlaqtA%253D%253D&md5=7832dbe09c9eebec1e5fcfd32aaed826Rho-kinase ROCK inhibitors reduce oligomeric tau proteinHamano, Tadanori; Shirafuji, Norimichi; Yen, Shu-Hui; Yoshida, Hirotaka; Kanaan, Nicholas M.; Hayashi, Kouji; Ikawa, Masamichi; Yamamura, Osamu; Fujita, Youshi; Kuriyama, Masaru; Nakamoto, YasunariNeurobiology of Aging (2020), 89 (), 41-54CODEN: NEAGDO; ISSN:0197-4580. (Elsevier)Neurofibrillary tangles, one of the pathol. hallmarks of Alzheimer's disease, consist of highly phosphorylated tau proteins. Tau protein binds to microtubules and is best known for its role in regulating microtubule dynamics. However, if tau protein is phosphorylated by activated major tau kinases, including glycogen synthase kinase 3β or cyclin-dependent kinase 5, or inactivated tau phosphatase, including protein phosphatase 2A, its affinity for microtubules is reduced, and the free tau is believed to aggregate, thereby forming neurofibrillary tangles. We previously reported that pitavastatin decreases the total and phosphorylated tau protein using a cellular model of tauopathy. The redn. of tau was considered to be due to Rho-assocd. coiled-coil protein kinase (ROCK) inhibition by pitavastatin. ROCK plays important roles to organize the actin cytoskeleton, an expected therapeutic target of human disorders. Several ROCK inhibitors are clin. applied to prevent vasospasm postsubarachnoid hemorrhage (fasudil) and for the treatment of glaucoma (ripasudil). We have examd. the effects of ROCK inhibitors (H1152, Y-27632, and fasudil [HA-1077]) on tau protein phosphorylation in detail. A human neuroblastoma cell line (M1C cells) that expresses wild-type tau protein (4R0N) by tetracycline-off (TetOff) induction, primary cultured mouse neurons, and a mouse model of tauopathy (rTG4510 line) were used. The levels of phosphorylated tau and caspase-cleaved tau were reduced by the ROCK inhibitors. Oligomeric tau levels were also reduced by ROCK inhibitors. After ROCK inhibitor treatment, glycogen synthase kinase 3β, cyclin-dependent kinase 5, and caspase were inactivated, protein phosphatase 2A was activated, and the levels of IFN-γ were reduced. ROCK inhibitors activated autophagy and proteasome pathways, which are considered important for the degrdn. of tau protein. Collectively, these results suggest that ROCK inhibitors represent a viable therapeutic route to reduce the pathogenic forms of tau protein in tauopathies, including Alzheimer's disease.
- 64McKerracher, L.; Shenkar, R.; Abbinanti, M.; Cao, Y.; Peiper, A.; Liao, J. K.; Lightle, R.; Moore, T.; Hobson, N.; Gallione, C.; Ruschel, J.; Koskimäki, J.; Girard, R.; Rosen, K.; Marchuk, D. A.; Awad, I. A. A brain-targeted orally available ROCK2 inhibitor benefits mild and aggressive cavernous angioma disease. Transl. Stroke Res. 2020, 11, 365– 376, DOI: 10.1007/s12975-019-00725-8[Crossref], [PubMed], [CAS], Google Scholar64https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1ektr7L&md5=a34ed2f97907a6a3ef12f13d98f639a4A Brain-Targeted Orally Available ROCK2 Inhibitor Benefits Mild and Aggressive Cavernous Angioma DiseaseMcKerracher, Lisa; Shenkar, Robert; Abbinanti, Matthew; Cao, Ying; Peiper, Amy; Liao, James K.; Lightle, Rhonda; Moore, Thomas; Hobson, Nicholas; Gallione, Carol; Ruschel, Joerg; Koskimaki, Janne; Girard, Romuald; Rosen, Kenneth; Marchuk, Douglas A.; Awad, Issam A.Translational Stroke Research (2020), 11 (3), 365-376CODEN: TSRRDY; ISSN:1868-601X. (Springer)We investigated a novel ROCK2 selective inhibitor for ability to reduce brain lesion formation, growth, and maturation. We used genetic methods to explore the use of a ROCK2-selective kinase inhibitor to reduce growth and hemorrhage of CAs. The role of ROCK2 in CA was investigated by crossing Rock1 or Rock2 hemizygous mice with Ccm1 or Ccm3 hemizygous mice, and we found reduced lesions in the Rock2 hemizygous mice. A ROCK2-selective inhibitor, BA-1049 was used to investigate efficacy in reducing CA lesions after oral administration to Ccm1+/- and Ccm3+/- mice that were bred into a mutator background. After assessing the dose range effective to target brain endothelial cells in an ischemic brain model, Ccm1+/- and Ccm3+/- transgenic mice were treated for 3 (Ccm3+/-) or 4 mo (Ccm1+/-), concurrently, randomized to receive one of three doses of BA-1049 in drinking water, or placebo. Lesion vols. were assessed by micro-computed tomog. BA-1049 reduced activation of ROCK2 in Ccm3+/-Trp53-/- lesions. Mice treated with BA-1049 or placebo showed a significant dose-dependent redn. in lesion vol. after treatment with BA-1049, and a redn. in hemorrhage (iron deposition) near lesions at all doses. These translational studies show that BA-1049 is a promising therapeutic agent for the treatment of CA, a disease with no current treatment except surgical removal of the brain lesions.
- 65Zhao, L.; Li, Y.; Wang, Y.; Qiao, Z.; Miao, Z.; Yang, J.; Huang, L.; Tian, C.; Li, L.; Chen, D.; Yang, S. Discovery of 4H-chromen-4-one derivatives as a new class of selective rho kinase (ROCK) inhibitors, which showed potent activity in ex vivo diabetic retinopathy models. J. Med. Chem. 2019, 62, 10691– 10710, DOI: 10.1021/acs.jmedchem.9b01143[ACS Full Text], [CAS], Google Scholar65https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitFWgsL7K&md5=ed46c7ef57f79b8d77fded5ebe52ce6fDiscovery of 4H-Chromen-4-one Derivatives as a New Class of Selective Rho Kinase (ROCK) Inhibitors, which Showed Potent Activity in ex Vivo Diabetic Retinopathy ModelsZhao, Lanying; Li, Yueshan; Wang, Yujiao; Qiao, Zeen; Miao, Zhuang; Yang, Jiao; Huang, Luyi; Tian, Chenyu; Li, Linli; Chen, Danian; Yang, ShengyongJournal of Medicinal Chemistry (2019), 62 (23), 10691-10710CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Diabetic retinopathy (DR) is a major cause of blindness, and there is a lack of effective treatment at present. Rho-assocd. coiled-coil contg. serine/threonine protein kinases (ROCKs) have recently been suggested as potential targets for the DR treatment. We herein report the discovery of 4H-chromen-4-one derivs. as a new class of ROCK inhibitors. Structure-activity relationship analyses led to the identification of the most active compd., 4-(dimethylamino)-N-(3-{2-[(4-oxo-4H-chromen-7-yl)oxy]acetamido}phenyl) (12j). This compd. showed excellent kinase selectivity for ROCK I and ROCK II against 387 other kinases. In retinal explants, compd. 12j protected retinal neurons from high glucose-induced oxidative stress and apoptosis-mediated cell death. Furthermore, 12j administration suppressed the improper proliferation of M.ovrddot.uller cells and promoted the regression of vascular vessels in retinal explants cultured in a high glucose microenvironment. Collectively, our data suggest that 12j could be a potential lead compd. for the treatment of DR, hence deserving further in-depth studies.
- 66Mocsai, A.; Ruland, J.; Tybulewicz, V. L. The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat. Rev. Immunol. 2010, 10, 387– 402, DOI: 10.1038/nri2765[Crossref], [PubMed], [CAS], Google Scholar66https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXlvFOkurk%253D&md5=85857a2b9beb84e0fe74263a90fa8a53The SYK tyrosine kinase: a crucial player in diverse biological functionsMocsai, Attila; Ruland, Jurgen; Tybulewicz, Victor L. J.Nature Reviews Immunology (2010), 10 (6), 387-402CODEN: NRIABX; ISSN:1474-1733. (Nature Publishing Group)A review. Spleen tyrosine kinase (SYK) is known to have a crucial role in adaptive immune receptor signalling. However, recent reports indicate that SYK also mediates other, unexpectedly diverse biol. functions, including cellular adhesion, innate immune recognition, osteoclast maturation, platelet activation and vascular development. SYK is activated by C-type lectins and integrins, and activates new targets, including the CARD9-BCL-10-MALT1 pathway and the NLRP3 inflammasome. Studies using Drosophila melanogaster suggest that there is an evolutionarily ancient origin of SYK-mediated signalling. Moreover, SYK has a crucial role in autoimmune diseases and haematol. malignancies. This Review summarizes our current understanding of the diverse functions of SYK and how this is being translated for therapeutic purposes.
- 67Braselmann, S.; Taylor, V.; Zhao, H.; Wang, S.; Sylvain, C.; Baluom, M.; Qu, K.; Herlaar, E.; Lau, A.; Young, C.; Wong, B. R.; Lovell, S.; Sun, T.; Park, G.; Argade, A.; Jurcevic, S.; Pine, P.; Singh, R.; Grossbard, E. B.; Payan, D. G.; Masuda, E. S. R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation. J. Pharmacol. Exp. Ther. 2006, 319, 998– 1008, DOI: 10.1124/jpet.106.109058[Crossref], [PubMed], [CAS], Google Scholar67https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xht1yltL7P&md5=18fea516041ea075d2123158f321a186R406, an orally available spleen tyrosine kinase inhibitor blocks Fc receptor signaling and reduces immune complex-mediated inflammationBraselmann, Sylvia; Taylor, Vanessa; Zhao, Haoran; Wang, Su; Sylvain, Catherine; Baluom, Muhammad; Qu, Kunbin; Herlaar, Ellen; Lau, Angela; Young, Chi; Wong, Brian R.; Lovell, Scott; Sun, Thomas; Park, Gary; Argade, Ankush; Jurcevic, Stipo; Pine, Polly; Singh, Rajinder; Grossbard, Elliott B.; Payan, Donald G.; Masuda, Esteban S.Journal of Pharmacology and Experimental Therapeutics (2006), 319 (3), 998-1008CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)Recent compelling evidence has lead to renewed interest in the role of antibodies and immune complexes in the pathogenesis of several autoimmune disorders, such as rheumatoid arthritis. These immune complexes, consisting of autoantibodies to self-antigens, can mediate inflammatory responses largely through binding and activating the Ig Fc receptors (FcRs). Using cell-based structure activity relationships with cultured human mast cells, we have identified the small mol. R406 [N4-(2,2-dimethyl-3-oxo-4H-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2- (3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine] as a potent inhibitor of IgE (IgE)- and IgG-mediated activation of Fc receptor signaling (EC50 for degranulation = 56-64 nM). Here we show that the primary target for R406 is the spleen tyrosine kinase (Syk), which plays a key role in the signaling of activating Fc receptors and the B-cell receptor (BCR). R406 inhibited phosphorylation of Syk substrate linker for activation of T cells in mast cells and B-cell linker protein/SLP65 in B cells. R406 bound to the ATP binding pocket of Syk and inhibited its kinase activity as an ATP-competitive inhibitor (Ki = 30 nM). Furthermore, R406 blocked Syk-dependent FcR-mediated activation of monocytes/macrophages and neutrophils and BCR-mediated activation of B lymphocytes. R406 was selective as assessed using a large panel of Syk-independent cell-based assays representing both specific and general signaling pathways. Consistent with Syk inhibition, oral administration of R406 to mice reduced immune complex-mediated inflammation in a reverse-passive Arthus reaction and two antibody-induced arthritis models. Finally, we report a first-in-human study showing that R406 is orally bioavailable, achieving exposures capable of inhibiting Syk-dependent IgE-mediated basophil activation. Collectively, the results show R406 potential for modulating Syk activity in human disease.
- 68Markham, A. Fostamatinib: first global approval. Drugs 2018, 78, 959– 963, DOI: 10.1007/s40265-018-0927-1[Crossref], [PubMed], [CAS], Google Scholar68https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVOlsb7M&md5=e58fd226c946b7e2087a74d31eeba972Fostamatinib: First Global ApprovalMarkham, AnthonyDrugs (2018), 78 (9), 959-963CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)A review. Rigel Pharmaceuticals are developing the spleen tyrosine kinase (SYK) inhibitor fostamatinib (TAVALISSE) as a treatment for immune thrombocytopenia (ITP), autoimmune haemolytic anemia and IgA nephropathy. Based on pos. results in the phase III FIT clin. trial program, the drug was recently approved in the US as a treatment for thrombocytopenia in adult patients with chronic ITP who have had an insufficient response to a previous treatment. This article summarizes the milestones in the development of fostamatinib leading to this first approval.
- 69Alimova, M.; Sidhom, E.-H.; Satyam, A.; Dvela-Levitt, M.; Melanson, M.; Chamberlain, B. T.; Alper, S. L.; Santos, J.; Gutierrez, J.; Subramanian, A.; Grinkevich, E.; Bricio, E. R.; Kim, C.; Clark, A.; Watts, A.; Thompson, R.; Marshall, J.; Pablo, J. L.; Coraor, J.; Roignot, J.; Vernon, K. A.; Keller, K.; Campbell, A.; Emani, M.; Racette, M.; Bazua-Valenti, S.; Padovano, V.; Weins, A.; McAdoo, S. P.; Tam, F. W. K.; Ronco, L.; Wagner, F.; Tsokos, G. C.; Shaw, J. L.; Greka, A. A high content screen for mucin-1-reducing compounds identifies fostamatinib as a candidate for rapid repurposing for acute lung injury during the COVID-19 pandemic. bioRxiv 2020, DOI: 10.1101/2020.1106.1130.180380 .
- 70Liu, D.; Mamorska-Dyga, A. Syk inhibitors in clinical development for hematological malignancies. J. Hematol. Oncol. 2017, 10, 145, DOI: 10.1186/s13045-017-0512-1[Crossref], [PubMed], [CAS], Google Scholar70https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitV2gsrbJ&md5=ed423c793913414c2966af15bd4457c4Syk inhibitors in clinical development for hematological malignanciesLiu, Delong; Mamorska-Dyga, AleksandraJournal of Hematology & Oncology (2017), 10 (), 145/1-145/7CODEN: JHOOAO; ISSN:1756-8722. (BioMed Central Ltd.)Spleen tyrosine kinase (Syk) is a cytosolic non-receptor protein tyrosine kinase (PTK) and is mainly expressed in hematopoietic cells. Syk was recognized as a crit. element in the B-cell receptor signaling pathway. Syk is also a key component in signal transduction from other immune receptors like Fc receptors and adhesion receptors. Several oral Syk inhibitors including fostamatinib (R788), entospletinib (GS-9973), cerdulatinib (PRT062070), and TAK-659 are being assessed in clin. trials. The second generation compd., entospletinib, showed promising results in clin. trials against B-cell malignancies, mainly chronic lymphoid leukemia. Syk inhibitors are being evaluated in combination regimens in multiple malignancies.
- 71Norman, P. Spleen tyrosine kinase inhibitors: a review of the patent literature 2010 - 2013. Expert Opin. Ther. Pat. 2014, 24, 573– 595, DOI: 10.1517/13543776.2014.890184[Crossref], [PubMed], [CAS], Google Scholar71https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXmt1Ghu7o%253D&md5=6db9860a438ced1374f5b8727e3cd420Spleen tyrosine kinase inhibitors: a review of the patent literature 2010 - 2013Norman, PeterExpert Opinion on Therapeutic Patents (2014), 24 (5), 573-595CODEN: EOTPEG; ISSN:1354-3776. (Informa Healthcare)A review. Introduction: The non-receptor tyrosine kinase, spleen tyrosine kinase (Syk), is primarily expressed in hematopoietic cells and appears to be particularly important in B cells. Syk is involved in signal transduction processes and appears to regulate allergic, inflammatory and autoimmune responses. It also appears to play a significant role in the development of haematol. malignancies. Inhibitors of Syk are potentially useful in treating asthma, rheumatoid arthritis, lupus, chronic lymphocytic leukemia and lymphomas. Areas covered: This article reviews the increasing no. of patent filings between 2010 and 2013 claiming Syk inhibitors and focuses on the multiple structural classes of Syk inhibitors disclosed. It also comments on recent developments with Syk inhibitors, both clin. results and licensing deals. Expert opinion: The increased interest in the identification of Syk inhibitors has seen a sharp increase in patent filings claiming such compds. However, the no. of these is well below that of filings relating to other pro-inflammatory kinases (p38, JAK). These filings have also claimed an increasingly diverse range of chem. classes moving away from the 2,4-diaminopyrimidine motif present in drugs such as fostamatinib and PRT-06207. Many of the claimed compds. are Syk inhibitors with potencies considerably better than fostamatinib. However, good kinase selectivity is also likely to be essential if a Syk inhibitor is to prove useful enough to emulate the JAK inhibitor tofacitinib in gaining marketing authorization. Recent clin. failures with Syk inhibitors are expected to result in a decrease in the rate of patent filings claiming Syk inhibitors.
- 72Sharman, J.; Di Paolo, J. Targeting B-cell receptor signaling kinases in chronic lymphocytic leukemia: the promise of entospletinib. Ther. Adv. Hematol. 2016, 7, 157– 170, DOI: 10.1177/2040620716636542[Crossref], [PubMed], [CAS], Google Scholar72https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmvVWhtbc%253D&md5=6ad9438ca036afcf88753c128075d58cTargeting B-cell receptor signaling kinases in chronic lymphocytic leukemia: the promise of entospletinibSharman, Jeff; Di Paolo, JulieTherapeutic Advances in Hematology (2016), 7 (3), 157-170CODEN: TAHHAT; ISSN:2040-6207. (Sage Publications Ltd.)The B-cell receptor signaling pathway has emerged as an important therapeutic target in chronic lymphocytic leukemia and other B-cell malignancies. Novel agents have been developed targeting the signaling enzymes spleen tyrosine kinase (SYK), Bruton's tyrosine kinase, and phosphoinositide 3-kinase delta. This review discusses the rationale for targeting these enzymes, as well as the preclin. and clin. evidence supporting their role as therapeutic targets, with a particular focus on SYK inhibition with entospletinib.
- 73Blomgren, P.; Chandrasekhar, J.; Di Paolo, J. A.; Fung, W.; Geng, G.; Ip, C.; Jones, R.; Kropf, J. E.; Lansdon, E. B.; Lee, S.; Lo, J. R.; Mitchell, S. A.; Murray, B.; Pohlmeyer, C.; Schmitt, A.; Suekawa-Pirrone, K.; Wise, S.; Xiong, J. M.; Xu, J.; Yu, H.; Zhao, Z.; Currie, K. S. Discovery of lanraplenib (GS-9876): a once-daily Spleen tyrosine kinase inhibitor for autoimmune diseases. ACS Med. Chem. Lett. 2020, 11, 506– 513, DOI: 10.1021/acsmedchemlett.9b00621[ACS Full Text], [CAS], Google Scholar73https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXivVarsr4%253D&md5=6cf006a37622fa12e284721fbbb7f76cDiscovery of Lanraplenib (GS-9876): A Once-Daily Spleen Tyrosine Kinase Inhibitor for Autoimmune DiseasesBlomgren, Peter; Chandrasekhar, Jayaraman; Di Paolo, Julie A.; Fung, Wanchi; Geng, Guoju; Ip, Carmen; Jones, Randall; Kropf, Jeffrey E.; Lansdon, Eric B.; Lee, Seung; Lo, Jennifer R.; Mitchell, Scott A.; Murray, Bernard; Pohlmeyer, Chris; Schmitt, Aaron; Suekawa-Pirrone, Kimberly; Wise, Sarah; Xiong, Jin-Ming; Xu, Jianjun; Yu, Helen; Zhao, Zhongdong; Currie, Kevin S.ACS Medicinal Chemistry Letters (2020), 11 (4), 506-513CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Spleen tyrosine kinase (SYK) is a crit. regulator of signaling in a variety of immune cell types such as B-cells, monocytes, and macrophages. Accordingly, there have been numerous efforts to identify compds. that selectively inhibit SYK as a means to treat autoimmune and inflammatory diseases. We previously disclosed GS-9973 (entospletinib) as a selective SYK inhibitor that is under clin. evaluation in hematol. malignancies. However, a BID dosing regimen and drug interaction with proton pump inhibitors (PPI) prevented development of entospletinib in inflammatory diseases. Herein, we report the discovery of a second-generation SYK inhibitor, GS-9876 (lanraplenib), which has human pharmacokinetic properties suitable for once-daily administration and is devoid of any interactions with PPI. Lanraplenib is currently under clin. evaluation in multiple autoimmune indications.
- 74Pavel, A. B.; Song, T.; Kim, H. J.; Del Duca, E.; Krueger, J. G.; Dubin, C.; Peng, X.; Xu, H.; Zhang, N.; Estrada, Y. D.; Denis, L.; Rao, N.; Gupta, S.; Zammit, D. J.; Bissonnette, R.; Guttman-Yassky, E. Oral Janus kinase/SYK inhibition (ASN002) suppresses inflammation and improves epidermal barrier markers in patients with atopic dermatitis. J. Allergy Clin. Immunol. 2019, 144, 1011– 1024, DOI: 10.1016/j.jaci.2019.07.013[Crossref], [PubMed], [CAS], Google Scholar74https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1Cnt7bE&md5=004e714116fde700c464fca189d22fb6Oral Janus kinase/SYK inhibition (ASN002) suppresses inflammation and improves epidermal barrier markers in patients with atopic dermatitisPavel, Ana B.; Song, Teresa; Kim, Hyun-Je; Del Duca, Ester; Krueger, James G.; Dubin, Celina; Peng, Xiangyu; Xu, Hui; Zhang, Ning; Estrada, Yeriel D.; Denis, Louis; Rao, Niranjan; Gupta, Sandeep; Zammit, David J.; Bissonnette, Robert; Guttman-Yassky, EmmaJournal of Allergy and Clinical Immunology (2019), 144 (4), 1011-1024CODEN: JACIBY; ISSN:0091-6749. (Elsevier)We sought to evaluate the effect of ASN002 on the cellular and mol. biomarker profile of patients with moderate-to-severe AD and to correlate changes in biomarkers to improvements in clin. severity measures and pruritus. Thirty-six patients with moderate-to-severe AD were randomized to groups with dose escalation of ASN002 (20, 40, and 80 mg) and a placebo group. Skin biopsy specimens were performed at baseline, day 15, and day 29. It also rapidly and significantly suppressed key inflammatory pathways implicated in AD pathogenesis, including TH2 (IL4 receptor [IL4R], IL13, CCL13/monocyte chemoattractant protein 4, CCL17/thymus and activation-regulated chemokine, CCL18/pulmonary and activation-regulated chemokine, CCL22/macrophage-derived chemokine, and CCL26/eotaxin-3), TH17/TH22 (lipocalins, PI3/elafin, CCL20, S100A7/S100A8/S100A9, and IL36G/IL36RN), and TH1 (IFNG, CXCL9/CXCL11, and MX1) axes and barrier-related measures (filaggrin [FLG] and CLDN23). Significant improvements in AD gene signatures were obsd. predominantly in the 40- and 80-mg groups. Smaller and largely nonsignificant mol. changes were seen in the 20-mg and placebo groups. The Janus kinase/spleen tyrosine kinase inhibitor ASN002 significantly suppressed key AD inflammatory pathways, corresponding to clin. response. ASN002 might be an effective novel therapeutic agent for moderate-to-severe AD.
- 75Barker, M. D.; Liddle, J.; Atkinson, F. L.; Wilson, D. M.; Dickson, M. C.; Ramirez-Molina, C.; Lewis, H.; Davis, R. P.; Somers, D. O.; Neu, M.; Jones, E.; Watson, R. Discovery of potent and selective Spleen Tyrosine Kinase inhibitors for the topical treatment of inflammatory skin disease. Bioorg. Med. Chem. Lett. 2018, 28, 3458– 3462, DOI: 10.1016/j.bmcl.2018.09.022[Crossref], [PubMed], [CAS], Google Scholar75https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslOksLzI&md5=508d42b03e2fedad09221f01a6762026Discovery of potent and selective Spleen Tyrosine Kinase inhibitors for the topical treatment of inflammatory skin diseaseBarker, Michael D.; Liddle, John; Atkinson, Francis L.; Wilson, David Matthew; Dickson, Marion C.; Ramirez-Molina, Cesar; Lewis, Huw; Davis, Rob P.; Somers, Donald O.; Neu, Margarete; Jones, Emma; Watson, RobertBioorganic & Medicinal Chemistry Letters (2018), 28 (21), 3458-3462CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)The discovery and lead optimization of a novel series of SYK inhibitors is described. These were optimized for SYK potency and selectivity against Aurora B. Compds. were profiled in a human skin penetration study to identify a suitable candidate mol. for pre-clin. development. Compd. 44 (GSK2646264) was selected for progression and is currently in Phase I clin. trials.
- 76Paris, D.; Ait-Ghezala, G.; Bachmeier, C.; Laco, G.; Beaulieu-Abdelahad, D.; Lin, Y.; Jin, C.; Crawford, F.; Mullan, M. The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation. J. Biol. Chem. 2014, 289, 33927– 33944, DOI: 10.1074/jbc.M114.608091[Crossref], [PubMed], [CAS], Google Scholar76https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVClurfL&md5=66b700e3cb27a1037c16ad9681d1b35aThe Spleen Tyrosine Kinase (Syk) Regulates Alzheimer Amyloid-β Production and Tau HyperphosphorylationParis, Daniel; Ait-Ghezala, Ghania; Bachmeier, Corbin; Laco, Gary; Beaulieu-Abdelahad, David; Lin, Yong; Jin, Chao; Crawford, Fiona; Mullan, MichaelJournal of Biological Chemistry (2014), 289 (49), 33927-33944CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)We have previously shown that the L-type calcium channel (LCC) antagonist nilvadipine reduces brain amyloid-β (Aβ) accumulation by affecting both Aβ prodn. and Aβ clearance across the blood-brain barrier (BBB). Nilvadipine consists of a mixt. of two enantiomers, (+)-nilvadipine and (-)-nilvadipine, in equal proportion. (+)-Nilvadipine is the active enantiomer responsible for the inhibition of LCC, whereas (-)-nilvadipine is considered inactive. Both nilvadipine enantiomers inhibit Aβ prodn. and improve the clearance of Aβ across the BBB showing that these effects are not related to LCC inhibition. In addn., treatment of P301S mutant human Tau transgenic mice (transgenic Tau P301S) with (-)-nilvadipine reduces Tau hyperphosphorylation at several Alzheimer disease (AD) pertinent epitopes. A search for the mechanism of action of (-)-nilvadipine revealed that this compd. inhibits the spleen tyrosine kinase (Syk). We further validated Syk as a target-regulating Aβ by showing that pharmacol. inhibition of Syk or down-regulation of Syk expression reduces Aβ prodn. and increases the clearance of Aβ across the BBB mimicking (-)-nilvadipine effects. Moreover, treatment of transgenic mice overexpressing Aβ and transgenic Tau P301S mice with a selective Syk inhibitor resp. decreased brain Aβ accumulation and Tau hyperphosphorylation at multiple AD relevant epitopes. We show that Syk inhibition induces an increased phosphorylation of the inhibitory Ser-9 residue of glycogen synthase kinase-3β, a primary Tau kinase involved in Tau phosphorylation, by activating protein kinase A, providing a mechanism explaining the redn. of Tau phosphorylation at GSK3β-dependent epitopes following Syk inhibition. Altogether our data highlight Syk as a promising target for preventing both Aβ accumulation and Tau hyperphosphorylation in AD.
- 77Bryan, M. C.; Rajapaksa, N. S. Kinase inhibitors for the treatment of immunological disorders: recent advances. J. Med. Chem. 2018, 61, 9030– 9058, DOI: 10.1021/acs.jmedchem.8b00667[ACS Full Text], [CAS], Google Scholar77https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVOmsLzI&md5=aff62adff54c9152d2b2156b05d67400Kinase Inhibitors for the Treatment of Immunological Disorders: Recent AdvancesBryan, Marian C.; Rajapaksa, Naomi S.Journal of Medicinal Chemistry (2018), 61 (20), 9030-9058CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Small mol. inhibitors targeting autoimmune and inflammatory processes have been an area of intense focus within academia and industry. Much of this work has been aimed at key kinases operating as central nodes in inflammatory signaling pathways. While this focus has led to over 30 FDA-approved small mol. kinase inhibitors, only one is currently approved for autoimmune and inflammatory diseases. Despite this lack of success, there remains tremendous reason for excitement. Our growing understanding of the biol. involved in the inflammatory response, the factors that lead to safer small mol. kinase inhibitors, and the availability of selective tool mols. for interrogating specific nodes and pathways are all pushing the field forward. This article focuses on recent developments requiring novel approaches to create safe and effective small mol. kinase inhibitors and where further work is needed to realize the promise of small mol. kinase inhibitors for patient benefit.
- 78Saxton, R. A.; Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 2017, 169, 361– 371, DOI: 10.1016/j.cell.2017.03.035[Crossref], [PubMed], [CAS], Google Scholar78https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXlvVKhsr8%253D&md5=5e3235c6302939ada00fc0e8d3f04293mTOR Signaling in Growth, Metabolism, and Disease [Erratum to document cited in CA166:281944]Saxton, Robert A.; Sabatini, David M.Cell (Cambridge, MA, United States) (2017), 169 (2), 361-371CODEN: CELLB5; ISSN:0092-8674. (Cell Press)Earlier drafts of the figures in this Review were published in print and online; the figures have been updated online. The information that the earlier figures contained was accurate and complete.
- 79Xu, K.; Liu, P.; Wei, W. mTOR signaling in tumorigenesis. Biochim. Biophys. Acta, Rev. Cancer 2014, 1846, 638– 654, DOI: 10.1016/j.bbcan.2014.10.007[Crossref], [PubMed], [CAS], Google Scholar79https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvV2msLjI&md5=18af080856fbb55a7f717689555c25fdmTOR signaling in tumorigenesisXu, Kai; Liu, Pengda; Wei, WenyiBiochimica et Biophysica Acta, Reviews on Cancer (2014), 1846 (2), 638-654CODEN: BBACEU; ISSN:0304-419X. (Elsevier B.V.)A review. MTOR (the mechanistic target of rapamycin) is an atypical serine/threonine kinase involved in regulating major cellular functions including growth and proliferation. Deregulation of the mTOR signaling pathway is one of the most commonly obsd. pathol. alterations in human cancers. To this end, oncogenic activation of the mTOR signaling pathway contributes to cancer cell growth, proliferation and survival, highlighting the potential for targeting the oncogenic mTOR pathway members as an effective anti-cancer strategy. In order to do so, a thorough understanding of the physiol. roles of key mTOR signaling pathway components and upstream regulators would guide future targeted therapies. Thus, in this review, we summarize available genetic mouse models for mTORC1 and mTORC2 components, as well as characterized mTOR upstream regulators and downstream targets, and assign a potential oncogenic or tumor suppressive role for each evaluated mol. Together, our work will not only facilitate the current understanding of mTOR biol. and possible future research directions, but more importantly, provide a mol. basis for targeted therapies aiming at key oncogenic members along the mTOR signaling pathway.
- 80Abdel-Maksoud, M. S.; El-Gamal, M. I.; Benhalilou, D. R.; Ashraf, S.; Mohammed, S. A.; Oh, C. H. Mechanistic/mammalian target of rapamycin: Recent pathological aspects and inhibitors. Med. Res. Rev. 2019, 39, 631– 664, DOI: 10.1002/med.21535[Crossref], [PubMed], [CAS], Google Scholar80https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3czisVSmug%253D%253D&md5=bacb5a2917bf3efa439587b6a54c2dc1Mechanistic/mammalian target of rapamycin: Recent pathological aspects and inhibitorsAbdel-Maksoud Mohammed S; El-Gamal Mohammed I; Benhalilou Dalia Reyane; Ashraf Sandy; Mohammed Shatha Abdulghaffar; El-Gamal Mohammed I; Oh Chang-Hyun; Oh Chang-HyunMedicinal research reviews (2019), 39 (2), 631-664 ISSN:.The mechanistic/mammalian target of rapamycin (mTOR), also known as the mechanistic target of rapamycin, regulates many normal cell processes such as transcription, cell growth, and autophagy. Overstimulation of mTOR by its ligands, amino acids, sugars, and/or growth factors leads to physiological disorders, including cancer and neurodegenerative diseases. In this study, we reviewed the recent advances regarding the mechanism that involves mTOR in cancer, aging, and neurodegenerative diseases. The chemical and biological properties of recently reported small molecules that function as mTOR kinase inhibitors, including adenosine triphosphate-competitive inhibitors and dual mTOR/PI3K inhibitors, have also been reviewed. We focused on the reports published in the literature from 2012 to 2017.
- 81Populo, H.; Lopes, J. M.; Soares, P. The mTOR signalling pathway in human cancer. Int. J. Mol. Sci. 2012, 13, 1886– 1918, DOI: 10.3390/ijms13021886[Crossref], [PubMed], [CAS], Google Scholar81https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XivVKhtro%253D&md5=e6c6c9f80fe1a40d4431bd9dfe0d1e45The mTOR signalling pathway in human cancerPopulo, Helena; Lopes, Jose Manuel; Soares, PaulaInternational Journal of Molecular Sciences (2012), 13 (), 1886-1918CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)A review. The conserved serine/threonine kinase mTOR (the mammalian target of rapamycin), a downstream effector of the PI3K/AKT pathway, forms two distinct multiprotein complexes: mTORC1 and mTORC2. MTORC1 is sensitive to rapamycin, activates S6K1 and 4EBP1, which are involved in mRNA translation. It is activated by diverse stimuli, such as growth factors, nutrients, energy and stress signals, and essential signalling pathways, such as PI3K, MAPK and AMPK, in order to control cell growth, proliferation and survival. MTORC2 is considered resistant to rapamycin and is generally insensitive to nutrients and energy signals. It activates PKC-α and AKT and regulates the actin cytoskeleton. Deregulation of multiple elements of the mTOR pathway (PI3K amplification/mutation, PTEN loss of function, AKT overexpression, and S6K1, 4EBP1 and eIF4E overexpression) has been reported in many types of cancers, particularly in melanoma, where alterations in major components of the mTOR pathway were reported to have significant effects on tumor progression. Therefore, mTOR is an appealing therapeutic target and mTOR inhibitors, including the rapamycin analogs deforolimus, everolimus and temsirolimus, are submitted to clin. trials for treating multiple cancers, alone or in combination with inhibitors of other pathways. Importantly, temsirolimus and everolimus were recently approved by the FDA for the treatment of renal cell carcinoma, PNET and giant cell astrocytoma. Small mols. that inhibit mTOR kinase activity and dual PI3K-mTOR inhibitors are also being developed. In this review, we aim to survey relevant research, the mol. mechanisms of signalling, including upstream activation and downstream effectors, and the role of mTOR in cancer, mainly in melanoma.
- 82Easton, J. B.; Houghton, P. J. mTOR and cancer therapy. Oncogene 2006, 25, 6436– 6446, DOI: 10.1038/sj.onc.1209886[Crossref], [PubMed], [CAS], Google Scholar82https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtVOlsrrN&md5=7a676e4128d249409e320924b26356ebmTOR and cancer therapyEaston, J. B.; Houghton, P. J.Oncogene (2006), 25 (48), 6436-6446CODEN: ONCNES; ISSN:0950-9232. (Nature Publishing Group)A review. Proteins regulating the mammalian target of rapamycin (mTOR), as well as some of the targets of the mTOR kinase, are overexpressed or mutated in cancer. Rapamycin, the naturally occurring inhibitor of mTOR, along with a no. of recently developed rapamycin analogs (rapalogs) consisting of synthetically derived compds. contg. minor chem. modifications to the parent structure, inhibit the growth of cell lines derived from multiple tumor types in vitro, and tumor models in vivo. Results from clin. trials indicate that the rapalogs may be useful for the treatment of subsets of certain types of cancer. The sporadic responses from the initial clin. trials, based on the hypothesis of general translation inhibition of cancer cells are now beginning to be understood owing to a more complete understanding of the dynamics of mTOR regulation and the function of mTOR in the tumor microenvironment. This review will summarize the preclin. and clin. data and recent discoveries of the function of mTOR in cancer and growth regulation.
- 83Mandrioli, J.; D’Amico, R.; Zucchi, E.; Gessani, A.; Fini, N.; Fasano, A.; Caponnetto, C.; Chio, A.; Dalla Bella, E.; Lunetta, C.; Mazzini, L.; Marinou, K.; Soraru, G.; de Biasi, S.; Lo Tartaro, D.; Pinti, M.; Cossarizza, A. Rapamycin treatment for amyotrophic lateral sclerosis: Protocol for a phase II randomized, double-blind, placebo-controlled, multicenter, clinical trial (RAP-ALS trial). Medicine (Philadelphia, PA, U. S.) 2018, 97, e11119 DOI: 10.1097/MD.0000000000011119[Crossref], [CAS], Google Scholar83https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFWrtbrK&md5=aa30fc88e15b0dc8ac2352b3bb993addRapamycin treatment for amyotrophic lateral sclerosis: Protocol for a phase II randomized, double-blind, placebo-controlled, multicenter, clinical trial (RAP-ALS trial)Mandrioli, Jessica; D'Amico, Roberto; Zucchi, Elisabetta; Gessani, Annalisa; Fini, Nicola; Fasano, Antonio; Caponnetto, Claudia; Chio, Adriano; Dalla Bella, Eleonora; Lunetta, Christian; Mazzini, Letizia; Marinou, Kalliopi; Soraru, Gianni; de Biasi, Sara; Lo Tartaro, Domenico; Pinti, Marcello; Cossarizza, AndreaMedicine (Philadelphia, PA, United States) (2018), 97 (24), e11119CODEN: MEDIAV; ISSN:0025-7974. (Lippincott Williams & Wilkins)Misfolded aggregated proteins and neuroinflammation significantly contribute to amyotrophic lateral sclerosis (ALS) pathogenesis, hence representing therapeutic targets to modify disease expression. Rapamycin inhibits mechanistic target of Rapamycin (mTOR) pathway and enhances autophagy with demonstrated beneficial effects in neurodegeneration in cell line and animal models, improving phenotype in SQSTM1 zebrafish, in Drosophila model of ALS-TDP, and in the TDP43 mouse model, in which it reduced neuronal loss and TDP43 inclusions. Rapamycin also expands regulatory T lymphocytes (Treg) and increased Treg levels are assocd. with slow progression in ALS patients.Therefore, we planned a randomized clin. trial testing Rapamycin treatment in ALS patients. RAP-ALS is a phase II randomized, double-blind, placebo-controlled, multicenter (8 ALS centers in Italy), clin. trial. The primary aim is to assess whether Rapamycin administration increases Tregs no. in treated patients compared with control arm. Secondary aims include the assessment of safety and tolerability of Rapamycin in patients with ALS; the min. dosage to have Rapamycin in cerebrospinal fluid; changes in immunol. (activation and homing of T, B, NK cell subpopulations) and inflammatory markers, and on mTOR downstream pathway (S6RP phosphorylation); clin. activity (ALS Functional Rating Scale-Revised, survival, forced vital capacity); and quality of life (ALSAQ40 scale). Rapamycin potentially targets mechanisms at play in ALS (i.e., autophagy and neuroinflammation), with promising preclin. studies. It is an already approved drug, with known pharmacokinetics, already available and therefore with significant possibility of rapid translation to daily clinics. Findings will provide reliable data for further potential trials. The study protocol was approved by the Ethics Committee of Azienda Ospedaliero Universitaria of Modena and by the Ethics Committees of participating centers (Eudract n. 2016-002399-28) based on the Helsinki declaration.
- 84Bonazzi, S.; Goold, C. P.; Gray, A.; Thomsen, N. M.; Nunez, J.; Karki, R. G.; Gorde, A.; Biag, J. D.; Malik, H. A.; Sun, Y.; Liang, G.; Lubicka, D.; Salas, S.; Labbe-Giguere, N.; Keaney, E. P.; McTighe, S.; Liu, S.; Deng, L.; Piizzi, G.; Lombardo, F.; Burdette, D.; Dodart, J. C.; Wilson, C. J.; Peukert, S.; Curtis, D.; Hamann, L. G.; Murphy, L. O. Discovery of a brain-penetrant ATP-competitive inhibitor of the mechanistic target of rapamycin (mTOR) for CNS disorders. J. Med. Chem. 2020, 63, 1068– 1083, DOI: 10.1021/acs.jmedchem.9b01398[ACS Full Text], [CAS], Google Scholar84https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXht1CktLo%253D&md5=d52546d7050d5e45b4fd241506004ef1Discovery of a Brain-Penetrant ATP-Competitive Inhibitor of the Mechanistic Target of Rapamycin (mTOR) for CNS DisordersBonazzi, Simone; Goold, Carleton P.; Gray, Audrey; Thomsen, Noel M.; Nunez, Jill; Karki, Rajeshri G.; Gorde, Aakruti; Biag, Jonathan D.; Malik, Hasnain A.; Sun, Yingchuan; Liang, Guiqing; Lubicka, Danuta; Salas, Sarah; Labbe-Giguere, Nancy; Keaney, Erin P.; McTighe, Stephanie; Liu, Shanming; Deng, Lin; Piizzi, Grazia; Lombardo, Franco; Burdette, Doug; Dodart, Jean-Cosme; Wilson, Christopher J.; Peukert, Stefan; Curtis, Daniel; Hamann, Lawrence G.; Murphy, Leon O.Journal of Medicinal Chemistry (2020), 63 (3), 1068-1083CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Recent clin. evaluation of everolimus for seizure redn. in patients with tuberous sclerosis complex (TSC), a disease with overactivated mechanistic target of rapamycin (mTOR) signaling, has demonstrated the therapeutic value of mTOR inhibitors for central nervous system (CNS) indications. Given that everolimus is an incomplete inhibitor of the mTOR function, we sought to develop a new mTOR inhibitor that has improved properties and is suitable for CNS disorders. Starting from an inhouse purine-based compd., optimization of the physicochem. properties of a thiazolopyrimidine series led to the discovery of the small mol. 7, a potent and selective brain-penetrant ATP-competitive mTOR inhibitor. In neuronal cell-based models of mTOR hyperactivity, 7 cor. the mTOR pathway activity and the resulting neuronal overgrowth phenotype. The new mTOR inhibitor 7 showed good brain exposure and significantly improved the survival rate of mice with neuronal-specific ablation of the Tsc1 gene. These results demonstrate the potential utility of this tool compd. to test therapeutic hypotheses that depend on mTOR hyperactivity in the CNS.
- 85Cansfield, A. D.; Ladduwahetty, T.; Sunose, M.; Ellard, K.; Lynch, R.; Newton, A. L.; Lewis, A.; Bennett, G.; Zinn, N.; Thomson, D. W.; Ruger, A. J.; Feutrill, J. T.; Rausch, O.; Watt, A. P.; Bergamini, G. CZ415, a highly selective mTOR inhibitor showing in vivo efficacy in a collagen induced arthritis model. ACS Med. Chem. Lett. 2016, 7, 768– 773, DOI: 10.1021/acsmedchemlett.6b00149[ACS Full Text], [CAS], Google Scholar85https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XpsF2mtr4%253D&md5=75b75c43427a76438e110251abd052b4CZ415, a Highly Selective mTOR Inhibitor Showing in Vivo Efficacy in a Collagen Induced Arthritis ModelCansfield, Andrew D.; Ladduwahetty, Tammy; Sunose, Mihiro; Ellard, Katie; Lynch, Rosemary; Newton, Anthea L.; Lewis, Ann; Bennett, Gavin; Zinn, Nico; Thomson, Douglas W.; Ruger, Anne J.; Feutrill, John T.; Rausch, Oliver; Watt, Alan P.; Bergamini, GiovannaACS Medicinal Chemistry Letters (2016), 7 (8), 768-773CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)CZ415, a potent ATP-competitive mTOR inhibitor with unprecedented selectivity over any other kinase is described. In addn. to a comprehensive characterization of its activities in vitro, in vitro ADME, and in vivo pharmacokinetic data are reported. The suitability of this inhibitor for studying in vivo mTOR biol. is demonstrated in a mechanistic mouse model monitoring mTOR proximal downstream phosphorylation signaling. Furthermore, the compd. reported here is the first ATP-competitive mTOR inhibitor described to show efficacy in a semitherapeutic collagen induced arthritis (CIA) mouse model.
- 86Yang, M.; Huang, L.; Li, X.; Kuang, E. Chloroquine inhibits lytic replication of Kaposi’s sarcoma-associated herpesvirus by disrupting mTOR and p38-MAPK activation. Antiviral Res. 2016, 133, 223– 233, DOI: 10.1016/j.antiviral.2016.08.010[Crossref], [PubMed], [CAS], Google Scholar86https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVehur3J&md5=54b3de95bc36cf693afc5b6461ad7bedChloroquine inhibits lytic replication of Kaposi's sarcoma-associated herpesvirus by disrupting mTOR and p38-MAPK activationYang, Mengtian; Huang, Lu; Li, Xiaojuan; Kuang, ErshengAntiviral Research (2016), 133 (), 223-233CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)Lytic infection is essential for the persistent infection and pathogenesis of Kaposi's sarcoma-assocd. herpesvirus (KSHV), and inhibiting KSHV lytic replication may effectively prevent the occurrence of KSHV-related diseases. Chloroquine (CQ), a well-known antimalarial drug and autophagy inhibitor, exerts broad-spectrum antiviral effects and shows anti-cancer therapeutic potential. However, the ability of CQ and its derivs. to control infection of oncogenic γ-herpesvirus remains undefined. Here we reveal that CQ suppresses KSHV lytic gene expression and virion prodn., and shows cytotoxicity toward KSHV lytically infected B cells at clin. acceptable doses. CQ suppresses mTOR and p38-MAPK pathway activation during KSHV lytic replication but not latent infection. Furthermore, CQ blocks Epstein-Barr virus (EBV) lytic replication via a distinct mechanism that is invoked to block virion prodn. but does not affect viral gene expression. These results suggest that CQ is an effective antiviral drug against KSHV lytic infection. Our findings indicate that CQ treatment should be considered for controlling KSHV-related diseases, particularly for primary use in co-infection of KSHV with malaria.
- 87Liu, Q.; Chang, J. W.; Wang, J.; Kang, S. A.; Thoreen, C. C.; Markhard, A.; Hur, W.; Zhang, J.; Sim, T.; Sabatini, D. M.; Gray, N. S. Discovery of 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benz o[h][1,6]naphthyridin-2(1H)-one as a highly potent, selective mammalian target of rapamycin (mTOR) inhibitor for the treatment of cancer. J. Med. Chem. 2010, 53, 7146– 7155, DOI: 10.1021/jm101144f[ACS Full Text], [CAS], Google Scholar87https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtF2nu7nN&md5=596ca3d515dd124c11f314dc92f551b9Discovery of 1-(4-(4-Propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo[h][1,6]naphthyridin-2(1H)-one as a highly potent, selective mammalian target of rapamycin (mTOR) inhibitor for the treatment of cancerLiu, Qingsong; Chang, Jae Won; Wang, Jinhua; Kang, Seong A.; Thoreen, Carson C.; Markhard, Andrew; Hur, Wooyoung; Zhang, Jianming; Sim, Taebo; Sabatini, David M.; Gray, Nathanael S.Journal of Medicinal Chemistry (2010), 53 (19), 7146-7155CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The mTOR protein is a master regulator of cell growth and proliferation, and inhibitors of its kinase activity have the potential to become new class of anticancer drugs. Starting from quinoline I, which was identified in a biochem. mTOR assay, we developed a tricyclic benzonaphthyridinone inhibitor II (Torin1), which inhibited phosphorylation of mTORC1 and mTORC2 substrates in cells at concns. of 2 and 10 nM, resp. Moreover, Torin1 exhibits 1000-fold selectivity for mTOR over PI3K (EC50 = 1800 nM) and exhibits 100-fold binding selectivity relative to 450 other protein kinases. Torin1 was efficacious at a dose of 20 mg/kg in a U87MG xenograft model and demonstrated good pharmacodynamic inhibition of downstream effectors of mTOR in tumor and peripheral tissues. These results demonstrate that Torin1 is a useful probe of mTOR-dependent phenomena and that benzonaphthridinones represent a promising scaffold for the further development of mTOR-specific inhibitors with the potential for clin. utility.
- 88Choi, S.; Kim, K.; Cha, M.; Kim, M.; Lee, B. H. mTOR signaling intervention by Torin1 and XL388 in the insular cortex alleviates neuropathic pain. Neurosci. Lett. 2020, 718, 134742, DOI: 10.1016/j.neulet.2020.134742[Crossref], [PubMed], [CAS], Google Scholar88https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3MbotVOrsA%253D%253D&md5=b416e1cba9b916950dc703add029fcb2mTOR signaling intervention by Torin1 and XL388 in the insular cortex alleviates neuropathic painChoi Songyeon; Kim Kyeongmin; Cha Myeounghoon; Kim Minjee; Lee Bae HwanNeuroscience letters (2020), 718 (), 134742 ISSN:.Signaling by mammalian target of rapamycin (mTOR), a kinase regulator of protein synthesis, has been implicated in the development of chronic pain. The mTOR comprises two distinct protein complexes, mTOR complex 1 (mTORC1) and mTORC2. Although effective inhibitors of mTORC1 and C2 have been developed, studies on the effect of these inhibitors related to pain modulation are still lacking. This study was conducted to determine the inhibitory effects of Torin1 and XL388 in an animal model of neuropathic pain. Seven days after neuropathic surgery, Torin1 or XL388 were microinjected into the insular cortex (IC) of nerve-injured animals and behavioral changes were assessed. Administration of Torin1 or XL388 into the IC significantly increased mechanical thresholds and reduced mechanical allodynia. At the immunoblotting results, Torin1 and XL388 significantly reduced phosphorylation of mTOR, 4E-BP1, p70S6K, and PKCα, without affecting Akt. These results strongly suggest that Torin1 and XL388 may attenuate neuropathic pain via inhibition of mTORC1 and mTORC2 in the IC.
- 89Liu, Q.; Wang, J.; Kang, S. A.; Thoreen, C. C.; Hur, W.; Ahmed, T.; Sabatini, D. M.; Gray, N. S. Discovery of 9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2) as a potent, selective, and orally available mammalian target of rapamycin (mTOR) inhibitor for treatment of cancer. J. Med. Chem. 2011, 54, 1473– 1480, DOI: 10.1021/jm101520v[ACS Full Text], [CAS], Google Scholar89https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhvFeis7c%253D&md5=845ed4ca35e5544954db71cd6813528eDiscovery of 9-(6-Aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2) as a potent, selective, and orally available mammalian target of rapamycin (mTOR) inhibitor for treatment of cancerLiu, Qingsong; Wang, Jinhua; Kang, Seong A.; Thoreen, Carson C.; Hur, Wooyoung; Ahmed, Tausif; Sabatini, David M.; Gray, Nathanael S.Journal of Medicinal Chemistry (2011), 54 (5), 1473-1480CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The mTOR mediated PI3K/AKT/mTOR signal transduction pathway has been demonstrated to play a key role in a broad spectrum of cancers. Starting from the mTOR selective inhibitor 1 (Torin1), a focused medicinal chem. effort led to the discovery of an improved mTOR inhibitor 3 (Torin2, I), which possesses an EC50 of 0.25 nM for inhibiting cellular mTOR activity. Compd. 3 exhibited 800-fold selectivity over PI3K (EC50: 200 nM) and over 100-fold binding selectivity relative to 440 other protein kinases. Compd. 3 has significantly improved bioavailability (54%), metabolic stability, and plasma exposure relative to compd. 1.
- 90Hanson, K. K.; Ressurreicao, A. S.; Buchholz, K.; Prudencio, M.; Herman-Ornelas, J. D.; Rebelo, M.; Beatty, W. L.; Wirth, D. F.; Hanscheid, T.; Moreira, R.; Marti, M.; Mota, M. M. Torins are potent antimalarials that block replenishment of Plasmodium liver stage parasitophorous vacuole membrane proteins. Proc. Natl. Acad. Sci. U. S. A. 2013, 110, E2838– 2847, DOI: 10.1073/pnas.1306097110[Crossref], [PubMed], [CAS], Google Scholar90https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1elsr%252FF&md5=248aa67f94cc846c89b9bd4052244070Torins are potent antimalarials that block replenishment of Plasmodium liver stage parasitophorous vacuole membrane proteinsHanson, Kirsten K.; Ressurreicao, Ana S.; Buchholz, Kathrin; Prudencio, Miguel; Herman-Ornelas, Jonathan D.; Rebelo, Maria; Beatty, Wandy L.; Wirth, Dyann F.; Hanscheid, Thomas; Moreira, Rui; Marti, Matthias; Mota, Maria M.Proceedings of the National Academy of Sciences of the United States of America (2013), 110 (30), E2838-E2847,SE2838/1-SE2838/8CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Residence within a customized vacuole is a highly successful strategy used by diverse intracellular microorganisms. The parasitophorous vacuole membrane (PVM) is the crit. interface between Plasmodium parasites and their possibly hostile, yet ultimately sustaining, host cell environment. The authors show that torins, developed as ATP-competitive mammalian target of rapamycin (mTOR) kinase inhibitors, are fast-acting antiplasmodial compds. that unexpectedly target the parasite directly, blocking the dynamic trafficking of the Plasmodium proteins exported protein 1 (EXP1) and upregulated in sporozoites 4 (UIS4) to the liver stage PVM and leading to efficient parasite elimination by the hepatocyte. Torin2 has single-digit, or lower, nanomolar potency in both liver and blood stages of infection in vitro and is likewise effective against both stages in vivo, with a single oral dose sufficient to clear liver stage infection. Parasite elimination and perturbed trafficking of liver stage PVM-resident proteins are both specific aspects of torin-mediated Plasmodium liver stage inhibition, indicating that torins have a distinct mode of action compared with currently used antimalarials.
- 91Xue, Q.; Hopkins, B.; Perruzzi, C.; Udayakumar, D.; Sherris, D.; Benjamin, L. E. Palomid 529, a novel small-molecule drug, is a TORC1/TORC2 inhibitor that reduces tumor growth, tumor angiogenesis, and vascular permeability. Cancer Res. 2008, 68, 9551– 9557, DOI: 10.1158/0008-5472.CAN-08-2058[Crossref], [PubMed], [CAS], Google Scholar91https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtlOmt7nE&md5=5288bb78a6b4f2685fde809f08d8086aPalomid 529, a Novel Small-Molecule Drug, Is a TORC1/TORC2 Inhibitor That Reduces Tumor Growth, Tumor Angiogenesis, and Vascular PermeabilityXue, Qi; Hopkins, Benjamin; Perruzzi, Carole; Udayakumar, Durga; Sherris, David; Benjamin, Laura E.Cancer Research (2008), 68 (22), 9551-9557CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)It has become clear that the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is central for promoting both tumor and tumor stroma and is therefore a major target for anticancer drug development. First- and second-generation rapalogs (prototypical mTOR inhibitors) have shown promise but, due to the complex nature of mTOR signaling, can result in counterproductive feedback signaling to potentiate upstream Akt signaling. We present a novel PI3K/Akt/mTOR inhibitor, Palomid 529 (P529), which inhibits the TORC1 and TORC2 complexes and shows both inhibition of Akt signaling and mTOR signaling similarly in tumor and vasculature. We show that P529 inhibits tumor growth, angiogenesis, and vascular permeability. It retains the beneficial aspects of tumor vascular normalization that rapamycin boasts. However, P529 has the addnl. benefit of blocking pAktS473 signaling consistent with blocking TORC2 in all cells and thus bypassing feedback loops that lead to increased Akt signaling in some tumor cells.
- 92Dalal, M.; Jacobs-El, N.; Nicholson, B.; Tuo, J.; Chew, E.; Chan, C. C.; Nussenblatt, R.; Ferris, F.; Meyerle, C. Subconjunctival Palomid 529 in the treatment of neovascular age-related macular degeneration. Graefe's Arch. Clin. Exp. Ophthalmol. 2013, 251, 2705– 2709, DOI: 10.1007/s00417-013-2375-7[Crossref], [PubMed], [CAS], Google Scholar92https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFCit7nL&md5=a94310abffe147aaccacf41fcd5bef7fSubconjunctival Palomid 529 in the treatment of neovascular age-related macular degenerationDalal, Monica; Jacobs-El, Naima; Nicholson, Benjamin; Tuo, Jingsheng; Chew, Emily; Chan, Chi-Chao; Nussenblatt, Robert; Ferris, Frederick; Meyerle, CatherineGraefe's Archive for Clinical and Experimental Ophthalmology (2013), 251 (12), 2705-2709CODEN: GACODL; ISSN:0721-832X. (Springer)Background: Recent evidence suggests that neovascular age-related macular degeneration (AMD) may have an immune mediated component. Palomid 529, an investigational medication involving the immune Akt/mTOR pathway, is unique in dissocg. both targets of rapamycin complexes TORC1 and TORC2. This small short-term pilot study assesses the safety of subconjunctival Palomid 529 in the treatment of neovascular AMD, with some limited efficacy information. Methods: In this 12-wk phase I open-label prospective pilot study, five participants with neovascular age-related macular degeneration that were refractory to intravitreal anti-vascular endothelial growth factor (VEGF) received three serial monthly subconjunctival doses of 1.9 mg Palomid 529. All participants were also offered concomitant monthly intravitreal anti-VEGF injections. Safety was monitored via adverse events recording. Addnl. outcome measures included visual acuity, optical coherence tomog., fluorescein angiog., indocyanine green angiog. and fundus photog. Results: The study drug was well-tolerated by all participants. There were no drug-related adverse events and no serious adverse events. A depot formed at the injection site, which persisted at the end of the study. In these anti-VEGF refractory patients, no clin. important changes in best-cor. visual acuity, fluorescein leakage pattern, choroidal neovascularization size on indocyanine green angiog., or autofluorescence pattern on fundus autofluorescence were obsd. compared to baseline. The fluid status, assessed with optical coherence tomog. showed that central retinal thickness and macular vol. remained stable in three participants, while the other two participants clin. progressed. Conclusions: Serial subconjunctival injections of Palomid 529 were well-tolerated and resulted in depot formation. There were no concerns for any ocular or systemic toxicity during this small short-term study. Larger randomized studies are required to det. efficacy.
- 93Mortensen, D. S.; Perrin-Ninkovic, S. M.; Shevlin, G.; Zhao, J.; Packard, G.; Bahmanyar, S.; Correa, M.; Elsner, J.; Harris, R.; Lee, B. G.; Papa, P.; Parnes, J. S.; Riggs, J. R.; Sapienza, J.; Tehrani, L.; Whitefield, B.; Apuy, J.; Bisonette, R. R.; Gamez, J. C.; Hickman, M.; Khambatta, G.; Leisten, J.; Peng, S. X.; Richardson, S. J.; Cathers, B. E.; Canan, S. S.; Moghaddam, M. F.; Raymon, H. K.; Worland, P.; Narla, R. K.; Fultz, K. E.; Sankar, S. Discovery of mammalian target of rapamycin (mTOR) kinase inhibitor CC-223. J. Med. Chem. 2015, 58, 5323– 5333, DOI: 10.1021/acs.jmedchem.5b00626[ACS Full Text], [CAS], Google Scholar93https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVansrzI&md5=0f1ed6d929618ea8468fefefb196c606Discovery of Mammalian Target of Rapamycin (mTOR) Kinase Inhibitor CC-223Mortensen, Deborah S.; Perrin-Ninkovic, Sophie M.; Shevlin, Graziella; Zhao, Jingjing; Packard, Garrick; Bahmanyar, Sogole; Correa, Matthew; Elsner, Jan; Harris, Roy; Lee, Branden G. S.; Papa, Patrick; Parnes, Jason S.; Riggs, Jennifer R.; Sapienza, John; Tehrani, Lida; Whitefield, Brandon; Apuy, Julius; Bisonette, Rene R.; Gamez, James C.; Hickman, Matt; Khambatta, Godrej; Leisten, Jim; Peng, Sophie X.; Richardson, Samantha J.; Cathers, Brian E.; Canan, Stacie S.; Moghaddam, Mehran F.; Raymon, Heather K.; Worland, Peter; Narla, Rama Krishna; Fultz, Kimberly E.; Sankar, SabitaJournal of Medicinal Chemistry (2015), 58 (13), 5323-5333CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)We report here the synthesis and structure-activity relationship (SAR) of a novel series of mammalian target of rapamycin (mTOR) kinase inhibitors. A series of 4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones were optimized for in vivo efficacy. These efforts resulted in the identification of compds. with excellent mTOR kinase inhibitory potency, with exquisite kinase selectivity over the related lipid kinase PI3K. The improved PK properties of this series allowed for exploration of in vivo efficacy and ultimately the selection of CC-223, I, for clin. development.
- 94Toker, A.; Cantley, L. C. Signalling through the lipid products of phosphoinositide-3-OH kinase. Nature 1997, 387, 673– 676, DOI: 10.1038/42648[Crossref], [PubMed], [CAS], Google Scholar94https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXktVWgt7c%253D&md5=9c0d3fdb3a9a10027050c09ed3def89aSignalling through the lipid products of phosphoinositide-3-OH kinaseToker, Alex; Cantley, Lewis C.Nature (London) (1997), 387 (6634), 673-676CODEN: NATUAS; ISSN:0028-0836. (Macmillan Magazines)A review, with 47 refs. When a stimulatory agonist mol. binds at the exterior of the cell membrane, a second messenger transduces the signal to the interior of the cell. Second messengers can be derived from phospholipids in the membrane by the action of the enzymes phospholipase C or phosphoinositide-3-OH kinase (PI(3)K). PI(3)K is a key player in many cellular responses, including the movement of organelle membranes, shape alteration through rearrangement of cytoskeletal actin, transformation and chemotaxis. But how PI(3)K mediates these responses is only now becoming clear.
- 95Engelman, J. A. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat. Rev. Cancer 2009, 9, 550– 562, DOI: 10.1038/nrc2664[Crossref], [PubMed], [CAS], Google Scholar95https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXovFylsrg%253D&md5=f0d4cc1fabf879e95f8b76e48cc9c1adTargeting PI3K signalling in cancer: opportunities, challenges and limitationsEngelman, Jeffrey A.Nature Reviews Cancer (2009), 9 (8), 550-562CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)A review. There are ample genetic and lab. studies that suggest the PI3K-Akt pathway is vital to the growth and survival of cancer cells. Inhibitors targeting this pathway are entering the clinic at a rapid pace. In this Review, the therapeutic potential of drugs targeting PI3K-Akt signaling for the treatment of cancer is discussed. I focus on the advantages and drawbacks of different treatment strategies for targeting this pathway, the cancers that might respond best to these therapies and the challenges and limitations that confront their clin. development.
- 96Zhao, W.; Qiu, Y.; Kong, D. Class I phosphatidylinositol 3-kinase inhibitors for cancer therapy. Acta Pharm. Sin. B 2017, 7, 27– 37, DOI: 10.1016/j.apsb.2016.07.006[Crossref], [PubMed], [CAS], Google Scholar96https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1c7ovFOrsg%253D%253D&md5=9506d6088eb6f72dc579ece97bb19930Class I phosphatidylinositol 3-kinase inhibitors for cancer therapyZhao Wennan; Qiu Yuling; Kong DexinActa pharmaceutica Sinica. B (2017), 7 (1), 27-37 ISSN:2211-3835.The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in human cancers. Class I PI3Ks are lipid kinases that phosphorylate phosphatidylinositol 4,5-bisphosphate (PIP2) at the 3-OH of the inositol ring to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3), which in turn activates Akt and the downstream effectors like mammalian target of rapamycin (mTOR) to play key roles in carcinogenesis. Therefore, PI3K has become an important anticancer drug target, and currently there is very high interest in the pharmaceutical development of PI3K inhibitors. Idelalisib has been approved in USA and Europe as the first-in-class PI3K inhibitor for cancer therapy. Dozens of other PI3K inhibitors including BKM120 and ZSTK474 are being evaluated in clinical trials. Multifaceted studies on these PI3K inhibitors are being performed, such as single and combinational efficacy, resistance, biomarkers, etc. This review provides an introduction to PI3K and summarizes key advances in the development of PI3K inhibitors.
- 97Garces, A. E.; Stocks, M. J. Class 1 PI3K clinical candidates and recent inhibitor design strategies: a medicinal chemistry perspective. J. Med. Chem. 2019, 62, 4815– 4850, DOI: 10.1021/acs.jmedchem.8b01492[ACS Full Text], [CAS], Google Scholar97https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFOku7bK&md5=907395a39ed6fb683464ee92c6a2537fClass 1 PI3K Clinical Candidates and Recent Inhibitor Design Strategies: A Medicinal Chemistry PerspectiveGarces, Aimie E.; Stocks, Michael J.Journal of Medicinal Chemistry (2019), 62 (10), 4815-4850CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Phosphatidylinositol 3-kinases (PI3Ks) are a family of lipid kinases that phosphorylate the 3-OH of the inositol ring of phosphoinositides, and deregulation of this pathway has implications in many diseases. The search for novel PI3K inhibitors has been at the forefront of academic and industrial medicinal chem. with over 600 medicinal chem.-based publications and patents appearing to date, leading to 38 clin. candidates and the launch of two drugs, idelalisib in 2014 and copanlisib in 2017. This Perspective will discuss medicinal chem. design approaches to novel isoform-selective inhibitors through consideration of brief case histories of compds. that have progressed into clin. development or that have revealed new structural motifs in this highly competitive area of research.
- 98Down, K.; Amour, A.; Baldwin, I. R.; Cooper, A. W.; Deakin, A. M.; Felton, L. M.; Guntrip, S. B.; Hardy, C.; Harrison, Z. A.; Jones, K. L.; Jones, P.; Keeling, S. E.; Le, J.; Livia, S.; Lucas, F.; Lunniss, C. J.; Parr, N. J.; Robinson, E.; Rowland, P.; Smith, S.; Thomas, D. A.; Vitulli, G.; Washio, Y.; Hamblin, J. N. Optimization of novel indazoles as highly potent and selective inhibitors of Phosphoinositide 3-kinase δ for the treatment of respiratory disease. J. Med. Chem. 2015, 58, 7381– 7399, DOI: 10.1021/acs.jmedchem.5b00767[ACS Full Text], [CAS], Google Scholar98https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtlyjsrvJ&md5=2fe8e51a64e6f7c798bdcb63781d02adOptimization of Novel Indazoles as Highly Potent and Selective Inhibitors of Phosphoinositide 3-Kinase δ for the Treatment of Respiratory DiseaseDown, Kenneth; Amour, Augustin; Baldwin, Ian R.; Cooper, Anthony W. J.; Deakin, Angela M.; Felton, Leigh M.; Guntrip, Stephen B.; Hardy, Charlotte; Harrison, Zoe A.; Jones, Katherine L.; Jones, Paul; Keeling, Suzanne E.; Le, Joelle; Livia, Stefano; Lucas, Fiona; Lunniss, Christopher J.; Parr, Nigel J.; Robinson, Ed; Rowland, Paul; Smith, Sarah; Thomas, Daniel A.; Vitulli, Giovanni; Washio, Yoshiaki; Hamblin, J. NicoleJournal of Medicinal Chemistry (2015), 58 (18), 7381-7399CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Optimization of lead compd., through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clin. candidates I (GSK2269557) and II (GSK2292767) for the treatment of respiratory indications via inhalation. Compds. I and II are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation.
- 99Berndt, A.; Miller, S.; Williams, O.; Le, D. D; Houseman, B. T; Pacold, J. I; Gorrec, F.; Hon, W.-C.; Ren, P.; Liu, Y.; Rommel, C.; Gaillard, P.; Ruckle, T.; Schwarz, M. K; Shokat, K. M; Shaw, J. P; Williams, R. L The p110delta structure: mechanisms for selectivity and potency of new PI(3)K inhibitors. Nat. Chem. Biol. 2010, 6, 244, DOI: 10.1038/nchembio0310-244b[Crossref], [PubMed], [CAS], Google Scholar99https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhvFGnurk%253D&md5=9220d9d2eda6bdb3bc9e54437dfcff23The p110δ structure: mechanisms for selectivity and potency of new PI(3)K inhibitors. [Erratum to document cited in CA152:375583]Berndt, Alex; Miller, Siimon; Williams, Olusegun; Le, Daniel D.; Houseman, Benjamin T.; Pacold, Joseph I.; Gorrec, Fabrice; Hon, Wai-Chon; Liu, Yi; Rommel, Christian; Gaillard, Pascale; Rueckle, Thomas; Schwarz, Matthias K.; Shokat, Kevan M.; Shaw, Jeffrey P.; Williams, Roger L.Nature Chemical Biology (2010), 6 (3), 244CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)On page 117, in the author list, Pingda Ren, was omitted. The error has been cor. in the author list, author contributions and conflict of financial interest declaration in the HTML and PDF versions.
- 100Helmer, E.; Watling, M.; Jones, E.; Tytgat, D.; Jones, M.; Allen, R.; Payne, A.; Koch, A.; Healy, E. First-in-human studies of seletalisib, an orally bioavailable small-molecule PI3Kδ inhibitor for the treatment of immune and inflammatory diseases. Eur. J. Clin. Pharmacol. 2017, 73, 581– 591, DOI: 10.1007/s00228-017-2205-7[Crossref], [PubMed], [CAS], Google Scholar100https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXitFCrtLw%253D&md5=362235b5549c53252f30d4a3dd1c744eFirst-in-human studies of seletalisib, an orally bioavailable small-molecule PI3Kδ inhibitor for the treatment of immune and inflammatory diseasesHelmer, Eric; Watling, Mark; Jones, Emma; Tytgat, Dominique; Jones, Mark; Allen, Rodger; Payne, Andrew; Koch, Annelize; Healy, EugeneEuropean Journal of Clinical Pharmacology (2017), 73 (5), 581-591CODEN: EJCPAS; ISSN:0031-6970. (Springer)Purpose: PI3Ks are potential therapeutic targets in immune-inflammatory diseases. These studies aimed to investigate the safety, tolerability and PK profile of seletalisib, a selective inhibitor of PI3Kδ in humans. Methods: These phase I, randomized, double-blind, placebo-controlled, single-center studies (NCT02303509, NCT02207595) evaluated single and multiple oral doses of seletalisib (5-90 mg QD and 30 mg BID) in healthy adults and subjects with mild-to-moderate psoriasis (Study-1). Pharmacodynamic effects on markers of inflammation were assessed via changes in ex vivo basophil degranulation and histol. assessment of psoriatic skin biopsies. Results: Seletalisib was well tolerated at doses ≤15 mg (Study-1) and ≤45 mg QD (Study-2) for 14 days. No safety concerns or dose-limiting toxicities were identified (Study-1). Incidence of gastrointestinal-related AEs was not dose related but higher incidences of rash AEs were assocd. with higher-dose seletalisib (Study-2 rash AEs: 18 in 12 seletalisib-treated subjects vs. 1 in 1 placebo-treated subject). Mean seletalisib plasma concn.-time profiles increased with increasing doses after single and multiple dosing, with no major deviations from dose-proportionality. There was no unexpected accumulation or loss of exposure after multiple dosing (time-independent pharmacokinetic profile). Apparent t1/2 values were supportive of once-daily dosing (geometric mean t1/2: Study-1, 17.7-21.1 h; Study-2, 18.1-22.4 h). No clin. significant food effect was obsd. (Study-1). Pharmacodynamic findings demonstrated ex vivo inhibition of basophil degranulation, improvements in histol. assessment of skin biopsies and other markers of psoriatic biol. and preliminary evidence of target engagement in psoriatic skin tissue. Conclusions: Seletalisib safety, tolerability and pharmacokinetic/pharmacodynamic profiles support its continued clin. development in immune-inflammatory diseases.
- 101Rao, V. K.; Webster, S.; Dalm, V.; Sediva, A.; van Hagen, P. M.; Holland, S.; Rosenzweig, S. D.; Christ, A. D.; Sloth, B.; Cabanski, M.; Joshi, A. D.; de Buck, S.; Doucet, J.; Guerini, D.; Kalis, C.; Pylvaenaeinen, I.; Soldermann, N.; Kashyap, A.; Uzel, G.; Lenardo, M. J.; Patel, D. D.; Lucas, C. L.; Burkhart, C. Effective “activated PI3Kδ syndrome“-targeted therapy with the PI3Kδ inhibitor leniolisib. Blood 2017, 130, 2307– 2316, DOI: 10.1182/blood-2017-08-801191[Crossref], [PubMed], [CAS], Google Scholar101https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhs1erurnE&md5=cc03232e6fe6b27a3aad988755fb0fc6Effective "activated PI3Kδ syndrome"-targeted therapy with the PI3Kδ inhibitor leniolisibRao, V. Koneti; Webster, Sharon; Dalm, Virgil A. S. H.; Sediva, Anna; van Hagen, P. Martin; Holland, Steven; Rosenzweig, Sergio D.; Christ, Andreas D.; Sloth, Birgitte; Cabanski, Maciej; Joshi, Aniket D.; de Buck, Stefan; Doucet, Julie; Guerini, Danilo; Kalis, Christoph; Pylvaenaeinen, Ilona; Soldermann, Nicolas; Kashyap, Anuj; Uzel, Gulbu; Lenardo, Michael J.; Patel, Dhavalkumar D.; Lucas, Carrie L.; Burkhart, ChristophBlood (2017), 130 (21), 2307-2316CODEN: BLOOAW; ISSN:1528-0020. (American Society of Hematology)Pathogenic gain-of-function variants in the genes encoding phosphoinositide 3-kinase δ (PI3Kδ) lead to accumulation of transitional B cells and senescent T cells, lymphadenopathy, and immune deficiency (activated PI3Kδ syndrome [APDS]). Knowing the genetic etiol. of APDS afforded us the opportunity to explore PI3Kδ inhibition as a precision-medicine therapy. Here, we report in vitro and in vivo effects of inhibiting PI3Kδ in APDS. Treatment with leniolisib (CDZ173), a selective PI3Kδ inhibitor, caused dose-dependent suppression of PI3Kδ pathway hyperactivation (measured as phosphorylation of AKT/S6) in cell lines ectopically expressing APDS-causative p110δ variants and in T-cell blasts derived from patients. A clin. trial with 6 APDS patients was conducted as a 12-wk, open-label, multisite, within-subject, dose-escalation study of oral leniolisib to assess safety, pharmacokinetics, and effects on lymphoproliferation and immune dysregulation. Oral leniolisib led to a dose-dependent redn. in PI3K/AKT pathway activity assessed ex vivo and improved immune dysregulation. We obsd. normalization of circulating transitional and naive B cells, redn. in PD-1+CD4+ and senescent CD57+CD4- T cells, and decreases in elevated serum IgM and inflammatory markers including interferon γ, tumor necrosis factor, CXCL13, and CXCL10 with leniolisib therapy. After 12 wk of treatment, all patients showed amelioration of lymphoproliferation with lymph node sizes and spleen vols. reduced by 39% (mean; range, 26%-57%) and 40% (mean; range, 13%-65%), resp. Thus, leniolisib was well tolerated and improved lab. and clin. parameters in APDS, supporting the specific inhibition of PI3Kδ as a promising new targeted therapy in APDS and other diseases characterized by overactivation of the PI3Kδ pathway.
- 102Greenwell, I. B.; Ip, A.; Cohen, J. B. PI3K inhibitors: understanding toxicity mechanisms and management. Oncology (Williston Park) 2017, 31, 821– 828[PubMed], [CAS], Google Scholar102https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1M3ltlGntA%253D%253D&md5=6c477dd4ae70ee2393283cd0b43ec885PI3K Inhibitors: Understanding Toxicity Mechanisms and ManagementGreenwell I Brian; Ip Andrew; Cohen Jonathon BOncology (Williston Park, N.Y.) (2017), 31 (11), 821-8 ISSN:0890-9091.The phosphatidylinositol 3-kinase (PI3K) pathway has attracted immense interest as a therapeutic target for cancer treatment. Idelalisib was the first PI3K inhibitor approved by the US Food and Drug Administration and is utilized in the treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma. Copanlisib has subsequently been approved for relapsed follicular lymphoma in patients who have received at least two prior systemic therapies. There are multiple other PI3K agents currently in development; these target various combinations of PI3K isoforms. Despite the therapeutic benefit, there have been concerns about the severe and sometimes fatal adverse effects of this class of drug. Several side effects are unusual and have poorly understood mechanisms; these include autoimmune dysfunction, opportunistic infections, skin toxicity, hypertension, and hyperglycemia. An understanding of these unusual toxicities, as well as a good grasp of management principles, will be important as more PI3K inhibitors are approved and become incorporated into routine practice.
- 103Evans, C. A.; Liu, T.; Lescarbeau, A.; Nair, S. J.; Grenier, L.; Pradeilles, J. A.; Glenadel, Q.; Tibbitts, T.; Rowley, A. M.; DiNitto, J. P.; Brophy, E. E.; O’Hearn, E. L.; Ali, J. A.; Winkler, D. G.; Goldstein, S. I.; O’Hearn, P.; Martin, C. M.; Hoyt, J. G.; Soglia, J. R.; Cheung, C.; Pink, M. M.; Proctor, J. L.; Palombella, V. J.; Tremblay, M. R.; Castro, A. C. Discovery of a selective Phosphoinositide-3-kinase (PI3K)-γ inhibitor (IPI-549) as an immuno-oncology clinical candidate. ACS Med. Chem. Lett. 2016, 7, 862– 867, DOI: 10.1021/acsmedchemlett.6b00238[ACS Full Text], [CAS], Google Scholar103https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1aju7vO&md5=9850bb40b0727512d0ca844264c2ec8aDiscovery of a Selective Phosphoinositide-3-Kinase (PI3K)-γ Inhibitor (IPI-549) as an Immuno-Oncology Clinical CandidateEvans, Catherine A.; Liu, Tao; Lescarbeau, Andre; Nair, Somarajan J.; Grenier, Louis; Pradeilles, Johan A.; Glenadel, Quentin; Tibbitts, Thomas; Rowley, Ann M.; DiNitto, Jonathan P.; Brophy, Erin E.; OHearn, Erin L.; Ali, Janid A.; Winkler, David G.; Goldstein, Stanley I.; OHearn, Patrick; Martin, Christian M.; Hoyt, Jennifer G.; Soglia, John R.; Cheung, Culver; Pink, Melissa M.; Proctor, Jennifer L.; Palombella, Vito J.; Tremblay, Martin R.; Castro, Alfredo C.ACS Medicinal Chemistry Letters (2016), 7 (9), 862-867CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Optimization of isoquinolinone PI3K inhibitors led to the discovery of a potent inhibitor of PI3K-γ (IPI-549) with >100-fold selectivity over other lipid and protein kinases. IPI-549 demonstrates favorable pharmacokinetic properties and robust inhibition of PI3K-γ mediated neutrophil migration in vivo and is currently in Phase 1 clin. evaluation in subjects with advanced solid tumors.
- 104Lin, S.; Jin, J.; Liu, Y.; Tian, H.; Zhang, Y.; Fu, R.; Zhang, J.; Wang, M.; Du, T.; Ji, M.; Wu, D.; Zhang, K.; Sheng, L.; Li, Y.; Chen, X.; Xu, H. Discovery of 4-methylquinazoline based PI3K inhibitors for the potential treatment of idiopathic pulmonary fibrosis. J. Med. Chem. 2019, 62, 8873– 8879, DOI: 10.1021/acs.jmedchem.9b00969[ACS Full Text], [CAS], Google Scholar104https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVemu7jI&md5=63e1f5f4ecd6796f77ee3885f10a8823Discovery of 4-Methylquinazoline Based PI3K Inhibitors for the Potential Treatment of Idiopathic Pulmonary FibrosisLin, Songwen; Jin, Jing; Liu, Ying; Tian, Hua; Zhang, Yan; Fu, Rong; Zhang, Jingbo; Wang, Mingjin; Du, Tingting; Ji, Ming; Wu, Deyu; Zhang, Kehui; Sheng, Li; Li, Yan; Chen, Xiaoguang; Xu, HengJournal of Medicinal Chemistry (2019), 62 (19), 8873-8879CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease, and its mol. pathogenesis remains poorly understood. Recently, emerging evidence demonstrates that the PI3K signaling transduction pathway is linked to the pathol. of IPF. In this work, we rationally designed a new series of 4-methylquinazoline derivs. as highly potent PI3K inhibitors that significantly suppress the phosphorylation of the main PI3K downstream effectors and displays marked antiproliferative activity in mouse MLg2908 lung fibroblasts. In a bleomycin-induced mouse pulmonary fibrosis model, 5d from the series improved mouse lung function and slowed the progression of pulmonary fibrosis. Overall, this work promises a therapeutic potential for PI3K inhibitors to treat IPF.
- 105Come, J. H.; Collier, P. N.; Henderson, J. A.; Pierce, A. C.; Davies, R. J.; Le Tiran, A.; O’Dowd, H.; Bandarage, U. K.; Cao, J.; Deininger, D.; Grey, R.; Krueger, E. B.; Lowe, D. B.; Liang, J.; Liao, Y.; Messersmith, D.; Nanthakumar, S.; Sizensky, E.; Wang, J.; Xu, J.; Chin, E. Y.; Damagnez, V.; Doran, J. D.; Dworakowski, W.; Griffith, J. P.; Jacobs, M. D.; Khare-Pandit, S.; Mahajan, S.; Moody, C. S.; Aronov, A. M. Design and synthesis of a novel series of orally bioavailable, CNS-penetrant, isoform selective Phosphoinositide 3-kinase γ (PI3Kγ) inhibitors with potential for the treatment of multiple sclerosis (MS). J. Med. Chem. 2018, 61, 5245– 5256, DOI: 10.1021/acs.jmedchem.8b00085[ACS Full Text], [CAS], Google Scholar105https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVGjsr%252FP&md5=6cae03cd2a64df22832dbdb29ceb0d7cDesign and Synthesis of a Novel Series of Orally Bioavailable, CNS-Penetrant, Isoform Selective Phosphoinositide 3-Kinase γ (PI3Kγ) Inhibitors with Potential for the Treatment of Multiple Sclerosis (MS)Come, Jon H.; Collier, Philip N.; Henderson, James A.; Pierce, Albert C.; Davies, Robert J.; Le Tiran, Arnaud; O'Dowd, Hardwin; Bandarage, Upul K.; Cao, Jingrong; Deininger, David; Grey, Ron; Krueger, Elaine B.; Lowe, Derek B.; Liang, Jianglin; Liao, Yusheng; Messersmith, David; Nanthakumar, Suganthi; Sizensky, Emmanuelle; Wang, Jian; Xu, Jinwang; Chin, Elaine Y.; Damagnez, Veronique; Doran, John D.; Dworakowski, Wojciech; Griffith, James P.; Jacobs, Marc D.; Khare-Pandit, Suvarna; Mahajan, Sudipta; Moody, Cameron S.; Aronov, Alex M.Journal of Medicinal Chemistry (2018), 61 (12), 5245-5256CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The lipid kinase phosphoinositide 3-kinase γ (PI3Kγ) has attracted attention as a potential target to treat a variety of autoimmune disorders, including multiple sclerosis, due to its role in immune modulation and microglial activation. By minimizing the no. of hydrogen bond donors while targeting a previously uncovered selectivity pocket adjacent to the ATP binding site of PI3Kγ, we discovered a series of azaisoindolinones as selective, brain penetrant inhibitors of PI3Kγ. This ultimately led to the discovery of 16, an orally bioavailable compd. that showed efficacy in murine exptl. autoimmune encephalomyelitis (EAE), a preclin. model of multiple sclerosis.
- 106Erra, M.; Taltavull, J.; Bernal, F. J.; Caturla, J. F.; Carrascal, M.; Pages, L.; Mir, M.; Espinosa, S.; Gracia, J.; Dominguez, M.; Sabate, M.; Paris, S.; Maldonado, M.; Hernandez, B.; Bravo, M.; Calama, E.; Miralpeix, M.; Lehner, M. D.; Calbet, M. Discovery of a novel inhaled PI3Kδ inhibitor for the treatment of respiratory diseases. J. Med. Chem. 2018, 61, 9551– 9567, DOI: 10.1021/acs.jmedchem.8b00873[ACS Full Text], [CAS], Google Scholar106https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvFaltbbK&md5=f7f14dd277a8ef119a2aeabb1558a838Discovery of a Novel Inhaled PI3Kδ Inhibitor for the Treatment of Respiratory DiseasesErra, Montse; Taltavull, Joan; Bernal, Francisco Javier; Caturla, Juan Francisco; Carrascal, Marta; Pages, Lluis; Mir, Marta; Espinosa, Sonia; Gracia, Jordi; Dominguez, Maria; Sabate, Mar; Paris, Stephane; Maldonado, Monica; Hernandez, Begona; Bravo, Monica; Calama, Elena; Miralpeix, Montserrat; Lehner, Martin D.; Calbet, MartaJournal of Medicinal Chemistry (2018), 61 (21), 9551-9567CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Oral PI3Kδ inhibitors such as Idelalisib and Duvelisib have shown efficacy as anticancer agents and Idelalisib has been approved for the treatment of three B-cell cancers. However, Idelalisib has a black box warning on its product label regarding the risks of fatal and serious toxicities including hepatic toxicity, severe diarrhea, colitis, pneumonitis, infections, and intestinal perforation. Some of these side effects are mechanism-related and could hinder the development of Idelalisib for less severe conditions. For respiratory diseases, compds. administered by inhalation are delivered directly to the site of action and may improve the therapeutic index of a drug, minimizing undesired side effects. This work describes the discovery and optimization of inhaled PI3Kδ inhibitors intended for the treatment of severe asthma and COPD. Once the potency was in the desired range, efforts were focused on identifying the particular physicochem. properties that could translate into better lung retention. This medicinal chem. exercise led to the identification of LAS195319 as a candidate for clin. development.
- 107Liu, Q.; Shi, Q.; Marcoux, D.; Batt, D. G.; Cornelius, L.; Qin, L. Y.; Ruan, Z.; Neels, J.; Beaudoin-Bertrand, M.; Srivastava, A. S.; Li, L.; Cherney, R. J.; Gong, H.; Watterson, S. H.; Weigelt, C.; Gillooly, K. M.; McIntyre, K. W.; Xie, J. H.; Obermeier, M. T.; Fura, A.; Sleczka, B.; Stefanski, K.; Fancher, R. M.; Padmanabhan, S.; Rp, T.; Kundu, I.; Rajareddy, K.; Smith, R.; Hennan, J. K.; Xing, D.; Fan, J.; Levesque, P. C.; Ruan, Q.; Pitt, S.; Zhang, R.; Pedicord, D.; Pan, J.; Yarde, M.; Lu, H.; Lippy, J.; Goldstine, C.; Skala, S.; Rampulla, R. A.; Mathur, A.; Gupta, A.; Arunachalam, P. N.; Sack, J. S.; Muckelbauer, J. K.; Cvijic, M. E.; Salter-Cid, L. M.; Bhide, R. S.; Poss, M. A.; Hynes, J.; Carter, P. H.; Macor, J. E.; Ruepp, S.; Schieven, G. L.; Tino, J. A. Identification of a potent, selective, and efficacious Phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitor for the treatment of immunological disorders. J. Med. Chem. 2017, 60, 5193– 5208, DOI: 10.1021/acs.jmedchem.7b00618[ACS Full Text], [CAS], Google Scholar107https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXos1Sgtbc%253D&md5=4bcbe85e7b82c19e47065be4fbeccdc8Identification of a Potent, Selective, and Efficacious Phosphatidylinositol 3-Kinase δ (PI3Kδ) Inhibitor for the Treatment of Immunological DisordersLiu, Qingjie; Shi, Qing; Marcoux, David; Batt, Douglas G.; Cornelius, Lyndon; Qin, Lan-Ying; Ruan, Zheming; Neels, James; Beaudoin-Bertrand, Myra; Srivastava, Anurag S.; Li, Ling; Cherney, Robert J.; Gong, Hua; Watterson, Scott H.; Weigelt, Carolyn; Gillooly, Kathleen M.; McIntyre, Kim W.; Xie, Jenny H.; Obermeier, Mary T.; Fura, Aberra; Sleczka, Bogdan; Stefanski, Kevin; Fancher, R. M.; Padmanabhan, Shweta; Thatipamula, R. P.; Kundu, Ipsit; Rajareddy, Kallem; Smith, Rodney; Hennan, James K.; Xing, Dezhi; Fan, Jingsong; Levesque, Paul C.; Ruan, Qian; Pitt, Sidney; Zhang, Rosemary; Pedicord, Donna; Pan, Jie; Yarde, Melissa; Lu, Hao; Lippy, Jonathan; Goldstine, Christine; Skala, Stacey; Rampulla, Richard A.; Mathur, Arvind; Gupta, Anuradha; Arunachalam, Pirama Nayagam; Sack, John S.; Muckelbauer, Jodi K.; Cvijic, Mary Ellen; Salter-Cid, Luisa M.; Bhide, Rajeev S.; Poss, Michael A.; Hynes, John; Carter, Percy H.; Macor, John E.; Ruepp, Stefan; Schieven, Gary L.; Tino, Joseph A.Journal of Medicinal Chemistry (2017), 60 (12), 5193-5208CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)PI3Kδ plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunol. disorders. This article highlights the work toward the identification of a potent, selective, and efficacious PI3Kδ inhibitor. Through careful SAR, the successful replacement of a polar pyrazole group by a simple chloro or trifluoromethyl group led to improved Caco-2 permeability, reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity profile while maintaining potency in the CD69 hWB assay. The optimization of the aryl substitution then identified a 4'-CN group that improved the human/rodent correlation in microsomal metabolic stability. The lead mol. is very potent in PK/PD assays and highly efficacious in a mouse collagen-induced arthritis model.
- 108Amour, A.; Barton, N.; Cooper, A. W.; Inglis, G.; Jamieson, C.; Luscombe, C. N.; Morrell, J.; Peace, S.; Perez, D.; Rowland, P.; Tame, C. J.; Uddin, S.; Vitulli, G.; Wellaway, N. Evolution of a novel, orally bioavailable series of PI3Kδ inhibitors from an inhaled lead for the treatment of respiratory disease. J. Med. Chem. 2016, 59, 7239– 7251, DOI: 10.1021/acs.jmedchem.6b00799[ACS Full Text], [CAS], Google Scholar108https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFyitLnN&md5=ab4641778d1c80f0dd9551d6d75ff4efEvolution of a Novel, Orally Bioavailable Series of PI3Kδ Inhibitors from an Inhaled Lead for the Treatment of Respiratory DiseaseAmour, Augustin; Barton, Nick; Cooper, Anthony W. J.; Inglis, Graham; Jamieson, Craig; Luscombe, Christopher N.; Morrell, Josie; Peace, Simon; Perez, David; Rowland, Paul; Tame, Christopher J.; Uddin, Sorif; Vitulli, Giovanni; Wellaway, NatalieJournal of Medicinal Chemistry (2016), 59 (15), 7239-7251CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A four-step process of high-quality modeling of existing data, deconstruction, identification of replacement cores, and an innovative synthetic regrowth strategy led to the rapid discovery of a novel oral series of PI3Kδ inhibitors with promising selectivity and excellent in vivo characteristics.
- 109Shin, Y.; Suchomel, J.; Cardozo, M.; Duquette, J.; He, X.; Henne, K.; Hu, Y. L.; Kelly, R. C.; McCarter, J.; McGee, L. R.; Medina, J. C.; Metz, D.; San Miguel, T.; Mohn, D.; Tran, T.; Vissinga, C.; Wong, S.; Wannberg, S.; Whittington, D. A.; Whoriskey, J.; Yu, G.; Zalameda, L.; Zhang, X.; Cushing, T. D. Discovery, optimization, and in vivo evaluation of benzimidazole derivatives AM-8508 and AM-9635 as potent and selective PI3Kδ inhibitors. J. Med. Chem. 2016, 59, 431– 447, DOI: 10.1021/acs.jmedchem.5b01651[ACS Full Text], [CAS], Google Scholar109https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvFylurnP&md5=258ce4cf8c13cf799f342ebab3137264Discovery, Optimization, and in Vivo Evaluation of Benzimidazole Derivatives AM-8508 and AM-9635 as Potent and Selective PI3Kδ InhibitorsShin, Youngsook; Suchomel, Julia; Cardozo, Mario; Duquette, Jason; He, Xiao; Henne, Kirk; Hu, Yi-Ling; Kelly, Ron C.; McCarter, John; McGee, Lawrence R.; Medina, Julio C.; Metz, Daniela; San Miguel, Tisha; Mohn, Deanna; Tran, Thuy; Vissinga, Christine; Wong, Simon; Wannberg, Sharon; Whittington, Douglas A.; Whoriskey, John; Yu, Gang; Zalameda, Leeanne; Zhang, Xuxia; Cushing, Timothy D.Journal of Medicinal Chemistry (2016), 59 (1), 431-447CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Lead optimization efforts resulted in the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, 1 (AM-8508) and 2 (AM-9635), with good pharmacokinetic properties. The compds. inhibit B cell receptor (BCR)-mediated AKT phosphorylation (pAKT) in PI3Kδ-dependent in vitro cell based assays. These compds. which share a benzimidazole bicycle are effective when administered in vivo at unbound concns. consistent with their in vitro cell potency as a consequence of improved unbound drug concn. with lower unbound clearance. Furthermore, the compds. demonstrated efficacy in a Keyhole Limpet Hemocyanin (KLH) study in rats, where the blockade of PI3Kδ activity by inhibitors 1 and 2 led to effective inhibition of antigen-specific IgG and IgM formation after immunization with KLH.
- 110Xu, F.; Na, L.; Li, Y.; Chen, L. Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours. Cell Biosci. 2020, 10, 54, DOI: 10.1186/s13578-020-00416-0[Crossref], [PubMed], [CAS], Google Scholar110https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB38zivVSktQ%253D%253D&md5=fc383947b2d3516bf4691cca2b4b8804Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumoursXu Fei; Xu Fei; Na Lixin; Na Lixin; Li Yanfei; Chen LinjunCell & bioscience (2020), 10 (), 54 ISSN:2045-3701.The PI3 K/AKT/mTOR signalling pathway plays an important role in the regulation of signal transduction and biological processes such as cell proliferation, apoptosis, metabolism and angiogenesis. Compared with those of other signalling pathways, the components of the PI3K/AKT/mTOR signalling pathway are complicated. The regulatory mechanisms and biological functions of the PI3K/AKT/mTOR signalling pathway are important in many human diseases, including ischaemic brain injury, neurodegenerative diseases, and tumours. PI3K/AKT/mTOR signalling pathway inhibitors include single-component and dual inhibitors. Numerous PI3K inhibitors have exhibited good results in preclinical studies, and some have been clinically tested in haematologic malignancies and solid tumours. In this review, we briefly summarize the results of research on the PI3K/AKT/mTOR pathway and discuss the structural composition, activation, communication processes, regulatory mechanisms and biological functions of the PI3K/AKT/mTOR signalling pathway in the pathogenesis of neurodegenerative diseases and tumours.
- 111Sun, K.; Luo, J.; Guo, J.; Yao, X.; Jing, X.; Guo, F. The PI3K/AKT/mTOR signaling pathway in osteoarthritis: a narrative review. Osteoarthritis Cartilage 2020, 28, 400– 409, DOI: 10.1016/j.joca.2020.02.027[Crossref], [PubMed], [CAS], Google Scholar111https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB387ksVKrtw%253D%253D&md5=33103b1a7ddf14d7554be97386308538The PI3K/AKT/mTOR signaling pathway in osteoarthritis: a narrative reviewSun K; Guo J; Yao X; Jing X; Guo F; Luo JOsteoarthritis and cartilage (2020), 28 (4), 400-409 ISSN:.Osteoarthritis (OA) is a complicated degenerative disease that affects whole joint tissue. Currently, apart from surgical approaches to treat late stage OA, effective treatments to reverse OA are not available. Thus, the mechanisms leading to OA, and more effective approaches to treat OA should be investigated. According to available evidence, the PI3K/AKT/mTOR signaling pathway is essential for normal metabolism of joint tissues, but is also involved in development of OA. To provide a wide viewpoint to roles of PI3K/AKT/mTOR signaling pathway in osteoarthritis, a comprehensive literature search was performed using PubMed terms 'PI3K OR AKT OR mTOR' and 'osteoarthritis'. This review highlights the role of PI3K/AKT/mTOR signaling in cartilage degradation, subchondral bone dysfunction, and synovial inflammation, and discusses how this signaling pathway affects development of the disease. We also summarize recent evidences of therapeutic approaches to treat OA by targeting the PI3K/AKT/mTOR pathway, and discuss potential challenges in developing these strategies for clinical treatment of OA.
- 112Fu, R. G.; Sun, Y.; Sheng, W. B.; Liao, D. F. Designing multi-targeted agents: An emerging anticancer drug discovery paradigm. Eur. J. Med. Chem. 2017, 136, 195– 211, DOI: 10.1016/j.ejmech.2017.05.016[Crossref], [PubMed], [CAS], Google Scholar112https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnsV2rtL8%253D&md5=511561bd2cd186d5dafa905b7257bf32Designing multi-targeted agents: An emerging anticancer drug discovery paradigmFu, Rong-geng; Sun, Yuan; Sheng, Wen-bing; Liao, Duan-fangEuropean Journal of Medicinal Chemistry (2017), 136 (), 195-211CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)A review. The dominant paradigm in drug discovery is to design ligands with max. selectivity to act on individual drug targets. With the target-based approach, many new chem. entities have been discovered, developed, and further approved as drugs. However, there are a large no. of complex diseases such as cancer that cannot be effectively treated or cured only with one medicine to modulate the biol. function of a single target. As simultaneous intervention of two (or multiple) cancer progression relevant targets has shown improved therapeutic efficacy, the innovation of multi-targeted drugs has become a promising and prevailing research topic and numerous multi-targeted anticancer agents are currently at various developmental stages. However, most multi-pharmacophore scaffolds are usually discovered by serendipity or screening, while rational design by combining existing pharmacophore scaffolds remains an enormous challenge. In this review, four types of multi-pharmacophore modes are discussed, and the examples from literature will be used to introduce attractive lead compds. with the capability of simultaneously interfering with different enzyme or signaling pathway of cancer progression, which will reveal the trends and insights to help the design of the next generation multi-targeted anticancer agents.
- 113Knight, S. D.; Adams, N. D.; Burgess, J. L.; Chaudhari, A. M.; Darcy, M. G.; Donatelli, C. A.; Luengo, J. I.; Newlander, K. A.; Parrish, C. A.; Ridgers, L. H.; Sarpong, M. A.; Schmidt, S. J.; Van Aller, G. S.; Carson, J. D.; Diamond, M. A.; Elkins, P. A.; Gardiner, C. M.; Garver, E.; Gilbert, S. A.; Gontarek, R. R.; Jackson, J. R.; Kershner, K. L.; Luo, L.; Raha, K.; Sherk, C. S.; Sung, C. M.; Sutton, D.; Tummino, P. J.; Wegrzyn, R. J.; Auger, K. R.; Dhanak, D. Discovery of GSK2126458, a highly potent inhibitor of PI3K and the mammalian target of rapamycin. ACS Med. Chem. Lett. 2010, 1, 39– 43, DOI: 10.1021/ml900028r[ACS Full Text], [CAS], Google Scholar113https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmvF2qtw%253D%253D&md5=72fcca85702dba95529ac03281e0bdbcDiscovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of RapamycinKnight, Steven D.; Adams, Nicholas D.; Burgess, Joelle L.; Chaudhari, Amita M.; Darcy, Michael G.; Donatelli, Carla A.; Luengo, Juan I.; Newlander, Ken A.; Parrish, Cynthia A.; Ridgers, Lance H.; Sarpong, Martha A.; Schmidt, Stanley J.; Van Aller, Glenn S.; Carson, Jeffrey D.; Diamond, Melody A.; Elkins, Patricia A.; Gardiner, Christine M.; Garver, Eric; Gilbert, Seth A.; Gontarek, Richard R.; Jackson, Jeffrey R.; Kershner, Kevin L.; Luo, Lusong; Raha, Kaushik; Sherk, Christian S.; Sung, Chiu-Mei; Sutton, David; Tummino, Peter J.; Wegrzyn, Ronald J.; Auger, Kurt R.; Dhanak, DashyantACS Medicinal Chemistry Letters (2010), 1 (1), 39-43CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Phosphoinositide 3-kinase α (PI3Kα) is a crit. regulator of cell growth and transformation, and its signaling pathway is the most commonly mutated pathway in human cancers. The mammalian target of rapamycin (mTOR), a class IV PI3K protein kinase, is also a central regulator of cell growth, and mTOR inhibitors are believed to augment the antiproliferative efficacy of PI3K/AKT pathway inhibition. 2,4-Difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide (GSK2126458, 1 (I)) has been identified as a highly potent, orally bioavailable inhibitor of PI3Kα and mTOR with in vivo activity in both pharmacodynamic and tumor growth efficacy models. Compd. 1 is currently being evaluated in human clin. trials for the treatment of cancer.
- 114Langdon, S. P.; Kay, C.; Um, I. H.; Dodds, M.; Muir, M.; Sellar, G.; Kan, J.; Gourley, C.; Harrison, D. J. Evaluation of the dual mTOR/PI3K inhibitors Gedatolisib (PF-05212384) and PF-04691502 against ovarian cancer xenograft models. Sci. Rep. 2019, 9, 18742, DOI: 10.1038/s41598-019-55096-9[Crossref], [PubMed], [CAS], Google Scholar114https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitl2gsrzN&md5=c2044300ca0cec59fe162e5a95223ad5Evaluation of the dual mTOR/PI3K inhibitors Gedatolisib (PF-05212384) and PF-04691502 against ovarian cancer xenograft modelsLangdon, Simon P.; Kay, Charlene; Um, In Hwa; Dodds, Michael; Muir, Morwenna; Sellar, Grant; Kan, Julie; Gourley, Charlie; Harrison, David J.Scientific Reports (2019), 9 (1), 18742CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)This study investigated the antitumor effects of two dual mTOR/PI3K inhibitors, gedatolisib (WYE-129587/PKI-587/PF-05212384) and PF-04691502 against a panel of six human patient derived ovarian cancer xenograft models. Both dual mTOR/PI3K inhibitors demonstrated antitumor activity against all xenografts tested. The compds. produced tumor stasis during the treatment period and upon cessation of treatment, tumors re-grew. In several models, there was an initial rapid redn. of tumor vol. over the first week of treatment before tumor stasis. No toxicity was obsd. during treatment. Biomarker studies were conducted in two xenograft models; phospho-S6 (Ser235/236) expression (as a readout of mTOR activity) was reduced over the treatment period in the responding xenograft but expression increased to control (no treatment) levels on cessation of treatment. Phospho-AKT (Ser473) expression (as a readout of PI3K) was inhibited by both drugs but less markedly so than phospho-S6 expression. Initial tumor vol. redn. on treatment and regrowth rate after treatment cessation was assocd. with phospho-S6/total S6 expression ratio. Both drugs produced apoptosis but minimally influenced markers of proliferation (Ki67, phospho-histone H3). These results indicate that mTOR/PI3K inhibition can produce broad spectrum tumor growth stasis in ovarian cancer xenograft models during continuous chronic treatment and this is assocd. with apoptosis.
- 115Munster, P.; Aggarwal, R.; Hong, D.; Schellens, J. H.; van der Noll, R.; Specht, J.; Witteveen, P. O.; Werner, T. L.; Dees, E. C.; Bergsland, E.; Agarwal, N.; Kleha, J. F.; Durante, M.; Adams, L.; Smith, D. A.; Lampkin, T. A.; Morris, S. R.; Kurzrock, R. First-in-human phase I study of GSK2126458, an oral pan-class I Phosphatidylinositol-3-kinase inhibitor, in patients with advanced solid tumor malignancies. Clin. Cancer Res. 2016, 22, 1932– 1939, DOI: 10.1158/1078-0432.CCR-15-1665[Crossref], [PubMed], [CAS], Google Scholar115https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmsFeqsLs%253D&md5=3306a5e6586e8865bea5ef70aadf68d6First-in-Human Phase I Study of GSK2126458, an Oral Pan-Class I Phosphatidylinositol-3-Kinase Inhibitor, in Patients with Advanced Solid Tumor MalignanciesMunster, Pamela; Aggarwal, Rahul; Hong, David; Schellens, Jan H. M.; van der Noll, Ruud; Specht, Jennifer; Witteveen, Petronella O.; Werner, Theresa L.; Dees, E. Claire; Bergsland, Emily; Agarwal, Neeraj; Kleha, Joseph F.; Durante, Michael; Adams, Laurel; Smith, Deborah A.; Lampkin, Thomas A.; Morris, Shannon R.; Kurzrock, RazelleClinical Cancer Research (2016), 22 (8), 1932-1939CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)GSK2126458 (GSK458) is a potent inhibitor of PI3K (α, β, γ, and δ), with preclin. studies demonstrating broad antitumor activity. We performed a first-in-human phase I study in patients with advanced solid tumors. Patients received oral GSK458 once or twice daily in a dose-escalation design to define the max. tolerated dose (MTD). Expansion cohorts evaluated pharmacodynamics, pharmacokinetics, and clin. activity in histol. and molecularly defined cohorts. One hundred and seventy patients received doses ranging from 0.1 to 3 mg once or twice daily. Dose-limiting toxicities (grade 3 diarrhea, n = 4; fatigue and rash, n = 1) occurred in 5 patients (n = 3 at 3 mg/day). The MTD was 2.5 mg/day (MTD with twice daily dosing undefined). The most common grade ≥3 treatment-related adverse events included diarrhea (8%) and skin rash (5%). Pharmacokinetic analyses demonstrated increased duration of drug exposure above target level with twice daily dosing. Fasting insulin and glucose levels increased with dose and exposure of GSK458. Durable objective responses (ORs) were obsd. across multiple tumor types (sarcoma, kidney, breast, endometrial, oropharyngeal, and bladder cancer). Responses were not assocd. with PIK3CA mutations (OR rate: 5% wild-type vs. 6% mutant). Although the MTD of GSK458 was 2.5 mg once daily, twice-daily dosing may increase duration of target inhibition. Fasting insulin and glucose levels served as pharmacodynamic markers of drug exposure. Select patients achieved durable responses; however, PIK3CA mutations were neither necessary nor predictive of response. Combination treatment strategies and novel biomarkers may be needed to optimally target PI3K.
- 116Maher, T. M.; Bareille, P.; Costa, M. J.; Fahy, W. A.; Harrison, S. A.; Holman, B. F.; Lukey, P.; Mang, Y.; Saunders, P.; Simpson, J. K.; Toshner, R.; Woodcock, H. V.; Yang, S.; Marshall, R. P. A randomised, placebo-controlled, double-blind, repeat dose escalation study with omipalisib (GSK2126458) in patients with idiopathic pulmonary fibrosis (IPF). Am. J. Resp. Crit. Care 2017, 195, A7010
- 117Jere, S. W.; Houreld, N. N.; Abrahamse, H. Role of the PI3K/AKT (mTOR and GSK3β) signalling pathway and photobiomodulation in diabetic wound healing. Cytokine Growth Factor Rev. 2019, 50, 52– 59, DOI: 10.1016/j.cytogfr.2019.03.001[Crossref], [PubMed], [CAS], Google Scholar117https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXltFCrtb8%253D&md5=ae03796eef761c28bd5138c48c3ddd34Role of the PI3K/AKT (mTOR and GSK3β) signalling pathway and photobiomodulation in diabetic wound healingJere, Sandy W.; Houreld, Nicolette N.; Abrahamse, HeidiCytokine & Growth Factor Reviews (2019), 50 (), 52-59CODEN: CGFRFB; ISSN:1359-6101. (Elsevier Ltd.)A review. Activated phosphatidylinositol 3 kinase/Protein kinase B (PI3K/AKT) signalling with increased or reduced mTOR and GSK3β activity influences the wound repair process. Diabetic wounds, usually ulcerated, are characterised by reduced growth factors and cellular performance. The occurrence of diabetic ulcers is linked to peripheral arterial disease, neuropathy, and wound contamination. Lasers or light emitting diodes (LEDs) provide photon energy with therapeutic benefits (Photobiomodulation-PBM), and has been broadly commended to quicken diabetic wound healing. PBM is efficient in the visible red and near-IR electromagnetic spectrum, and fluencies ranging from 2 to 6 J/cm2. However, cellular and mol. mechanisms induced by PBM are not fully understood. In this review we discuss PBM and the PI3K/AKT pathway with specific focus on the mTOR and GSK3β downstream activity in diabetic wound healing.
- 118Villalobos-Labra, R.; Silva, L.; Subiabre, M.; Araos, J.; Salsoso, R.; Fuenzalida, B.; Sáez, T.; Toledo, F.; Gonzalez, M.; Quezada, C.; Pardo, F.; Chiarello, D. I.; Leiva, A.; Sobrevia, L. Akt/mTOR role in human foetoplacental vascular insulin resistance in diseases of pregnancy. J. Diabetes Res. 2017, 2017, 5947859, DOI: 10.1155/2017/5947859[Crossref], [PubMed], [CAS], Google Scholar118https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1M7nvFektQ%253D%253D&md5=13e3a2341fd41ae546c9f28cd7a6baa5Akt/mTOR Role in Human Foetoplacental Vascular Insulin Resistance in Diseases of PregnancyVillalobos-Labra Roberto; Silva Luis; Subiabre Mario; Araos Joaquin; Salsoso Rocio; Fuenzalida Barbara; Saez Tamara; Toledo Fernando; Pardo Fabian; Chiarello Delia I; Leiva Andrea; Sobrevia Luis; Silva Luis; Saez Tamara; Salsoso Rocio; Sobrevia Luis; Toledo Fernando; Gonzalez Marcelo; Quezada Claudia; Pardo Fabian; Sobrevia LuisJournal of diabetes research (2017), 2017 (), 5947859 ISSN:.Insulin resistance is characteristic of pregnancies where the mother shows metabolic alterations, such as preeclampsia (PE) and gestational diabetes mellitus (GDM), or abnormal maternal conditions such as pregestational maternal obesity (PGMO). Insulin signalling includes activation of insulin receptor substrates 1 and 2 (IRS1/2) as well as Src homology 2 domain-containing transforming protein 1, leading to activation of 44 and 42 kDa mitogen-activated protein kinases and protein kinase B/Akt (Akt) signalling cascades in the human foetoplacental vasculature. PE, GDM, and PGMO are abnormal conditions coursing with reduced insulin signalling, but the possibility of the involvement of similar cell signalling mechanisms is not addressed. This review aimed to determine whether reduced insulin signalling in PE, GDM, and PGMO shares a common mechanism in the human foetoplacental vasculature. Insulin resistance in these pathological conditions results from reduced Akt activation mainly due to inhibition of IRS1/2, likely due to the increased activity of the mammalian target of rapamycin (mTOR) resulting from lower activity of adenosine monophosphate kinase. Thus, a defective signalling via Akt/mTOR in response to insulin is a central and common mechanism of insulin resistance in these diseases of pregnancy. In this review, we summarise the cell signalling mechanisms behind the insulin resistance state in PE, GDM, and PGMO focused in the Akt/mTOR signalling pathway in the human foetoplacental endothelium.
- 119Kiyoi, H. Flt3 inhibitors: recent advances and problems for clinical application. Nagoya J. Med. Sci. 2015, 77, 7– 17[PubMed], [CAS], Google Scholar119https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhslalt7rL&md5=9a44962a3aa888bfdfd3fb49e388999aFLT3 inhibitors: recent advances and problems for clinical applicationKiyoi, HitoshiNagoya Journal of Medical Science (2015), 77 (1,2), 7-17CODEN: NJMSAG; ISSN:0027-7622. (Nagoya University School of Medicine, Graduate School of Medicine)FLT3, a type III receptor tyrosine kinase, expresses on most acute leukemia cells as well as normal hematopoietic stem/progenitor cells. Mutation in the FLT3 gene is the most frequent genetic alteration in acute myeloid leukemia (AML) and is well known as an important driver mutation for the development of myeloid malignancies. FLT3 mutation is a strong poor prognostic factor for the long-term survival in AML patients, while neither high-dose chemotherapy nor allogeneic hematopoietic stem cell transplantation can overcome a poor prognosis. Development of an FLT3 inhibitor is, therefore, much awaited. To date, several potent FLT3 inhibitors have been developed and some of them were evaluated for efficacy in clin. trials, although no FLT3 inhibitor has been yet approved. Moreover, several problems for clin. use, such as adverse effects, blood concn. and resistance have been apparent. Recently developed AC220 is a highly selective and sensitive FLT3 inhibitor. In Phase I and II trials, AC220 so far showed the best efficacy of AML cells harboring FLT3 mutation among clin. evaluated FLT3 inhibitors, while severe bone marrow suppression and QTc prolongation should be resolved for the clin. use. In this review, I summarize the characteristics of FLT3 inhibitors in clin. development and discuss important issues to be resolved for clin. use.
- 120Gucky, T.; Reznickova, E.; Radosova Muchova, T.; Jorda, R.; Klejova, Z.; Malinkova, V.; Berka, K.; Bazgier, V.; Ajani, H.; Lepsik, M.; Divoky, V.; Krystof, V. Discovery of N(2)-(4-amino-cyclohexyl)-9-cyclopentyl-N(6)-(4-morpholin-4-ylmethyl-phenyl)- 9H-purine-2,6-diamine as a potent FLT3 kinase inhibitor for Acute myeloid leukemia with FLT3 mutations. J. Med. Chem. 2018, 61, 3855– 3869, DOI: 10.1021/acs.jmedchem.7b01529[ACS Full Text], [CAS], Google Scholar120https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXotVahsr0%253D&md5=cbc982a08f1905840e273e23c825a134Discovery of N2-(4-Amino-cyclohexyl)-9-cyclopentyl-N6-(4-morpholin-4-ylmethyl-phenyl)-9H-purine-2,6-diamine as a Potent FLT3 Kinase Inhibitor for Acute Myeloid Leukemia with FLT3 MutationsGucky, Tomas; Reznickova, Eva; Radosova Muchova, Tereza; Jorda, Radek; Klejova, Zuzana; Malinkova, Veronika; Berka, Karel; Bazgier, Vaclav; Ajani, Haresh; Lepsik, Martin; Divoky, Vladimir; Krystof, VladimirJournal of Medicinal Chemistry (2018), 61 (9), 3855-3869CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)FLT3 tyrosine kinase is a potential drug target in acute myeloid leukemia (AML) because patients with FLT3-ITD mutations respond poorly to std. cytotoxic agents and there is a clear link between the disease and the oncogenic properties of FLT3. We present novel 2,6,9-trisubstituted purine derivs. with potent FLT3 inhibitory activity. The lead compd. 7d displays nanomolar activity in biochem. assays and selectively blocks proliferation of AML cell lines harboring FLT3-ITD mutations, whereas other transformed and normal human cells are several orders of magnitude less sensitive. The MV4-11 cells treated with 7d suppressed the phosphorylation of FLT3 and its downstream signaling pathways, with subsequent G1 cell cycle arrest and apoptosis. Addnl., a single dose of 7d in mice with s.c. MV4-11 xenografts caused sustained inhibition of FLT3 and STAT5 phosphorylation over 48 h, in contrast to the shorter effect obsd. after administration of the ref. FLT3 inhibitor quizartinib.
- 121Ramos, M. I.; Tak, P. P.; Lebre, M. C. Fms-like tyrosine kinase 3 ligand-dependent dendritic cells in autoimmune inflammation. Autoimmun. Rev. 2014, 13, 117– 124, DOI: 10.1016/j.autrev.2013.09.010[Crossref], [PubMed], [CAS], Google Scholar121https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1Oru7jK&md5=f1c59aa866bb34514d9f4f7c2864ab12Fms-like tyrosine kinase 3 ligand-dependent dendritic cells in autoimmune inflammationRamos, M. I.; Tak, P. P.; Lebre, M. C.Autoimmunity Reviews (2014), 13 (2), 117-124CODEN: ARUEBU; ISSN:1568-9972. (Elsevier B.V.)A review. Dendritic cells (DCs) are specialized in capture, processing and presentation of antigens to T cells. Depending on the type of DC and its activation state, the interaction of DCs with naive T cells can lead to different types of immune response, or to T-cell tolerance. The existence of many specialized subtypes of DCs with particular functions has raised the need to distinguish DCs formed in steady-state from those produced during an inflammatory response. In patients with autoimmune disease and in exptl. animal models of autoimmunity, DCs show abnormalities in both nos. and activation state, expressing immunogenic levels of co-stimulatory mols. and pro-inflammatory cytokines. Initial in vitro studies of cytokines in DC development revealed distinct and important roles for the receptor tyrosine kinases, granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF, also called CSF1) and fms-like tyrosine kinase 3 ligand (Flt3L) in the generation of DCs. Flt3L is crit. for instructing DC generation throughout different organs and regulates DC development from Flt3+ lymphoid and myeloid-committed progenitors to DCs in vivo. The aim of this review is to provide an overview of the role of Flt3L-dependent DCs in the immunopathogenesis of autoimmunity and chronic inflammation and its potential as therapeutic targets.
- 122Kazi, J. U.; Ronnstrand, L. Fms-like tyrosine kinase 3/FLT3: from basic science to clinical implications. Physiol. Rev. 2019, 99, 1433– 1466, DOI: 10.1152/physrev.00029.2018[Crossref], [PubMed], [CAS], Google Scholar122https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFGlurrE&md5=ed99d5ecf4de02acb8196801e4e66e6aFMS-like tyrosine kinase 3/FLT3: from basic science to clinical implicationsKazi, Julhash U.; Roennstrand, LarsPhysiological Reviews (2019), 99 (3), 1433-1466CODEN: PHREA7; ISSN:1522-1210. (American Physiological Society)A review. FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase that is expressed almost exclusively in the hematopoietic compartment. Its ligand, FLT3 ligand (FL), induces dimerization and activation of its intrinsic tyrosine kinase activity. Activation of FLT3 leads to its autophosphorylation and initiation of several signal transduction cascades. Signaling is initiated by the recruitment of signal transduction mols. to activated FLT3 through binding to specific phosphorylated tyrosine residues in the intracellular region of FLT3. Activation of FLT3 mediates cell survival, cell proliferation, and differentiation of hematopoietic progenitor cells. It acts in synergy with several other cytokines to promote its biol. effects. Deregulated FLT3 activity has been implicated in several diseases, most prominently in acute myeloid leukemia where around one-third of patients carry an activating mutant of FLT3 which drives the disease and is correlated with poor prognosis. Overactivity of FLT3 has also been implicated in autoimmune diseases, such as rheumatoid arthritis. The observation that gain-of-function mutations of FLT3 can promote leukemogenesis has stimulated the development of inhibitors that target this receptor. Many of these are in clin. trials, and some have been approved for clin. use. However, problems with acquired resistance to these inhibitors are common and, furthermore, only a fraction of patients respond to these selective treatments. This review provides a summary of our current knowledge regarding structural and functional aspects of FLT3 signaling, both under normal and pathol. conditions, and discusses challenges for the future regarding the use of targeted inhibition of these pathways for the treatment of patients.
- 123Rivat, C.; Sar, C.; Mechaly, I.; Leyris, J. P.; Diouloufet, L.; Sonrier, C.; Philipson, Y.; Lucas, O.; Mallie, S.; Jouvenel, A.; Tassou, A.; Haton, H.; Venteo, S.; Pin, J. P.; Trinquet, E.; Charrier-Savournin, F.; Mezghrani, A.; Joly, W.; Mion, J.; Schmitt, M.; Pattyn, A.; Marmigere, F.; Sokoloff, P.; Carroll, P.; Rognan, D.; Valmier, J. Inhibition of neuronal FLT3 receptor tyrosine kinase alleviates peripheral neuropathic pain in mice. Nat. Commun. 2018, 9, 1042, DOI: 10.1038/s41467-018-03496-2[Crossref], [PubMed], [CAS], Google Scholar123https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1Mngtlegsg%253D%253D&md5=b07de24bfa7b2fb2e3f2c2cfe63bb9b2Inhibition of neuronal FLT3 receptor tyrosine kinase alleviates peripheral neuropathic pain in miceRivat Cyril; Sar Chamroeun; Mechaly Ilana; Leyris Jean-Philippe; Diouloufet Lucie; Sonrier Corinne; Lucas Olivier; Mallie Sylvie; Jouvenel Antoine; Tassou Adrien; Haton Henri; Venteo Stephanie; Mezghrani Alexandre; Joly Willy; Mion Julie; Pattyn Alexandre; Marmigere Frederic; Carroll Patrick; Valmier Jean; Rivat Cyril; Sar Chamroeun; Mechaly Ilana; Mallie Sylvie; Jouvenel Antoine; Tassou Adrien; Haton Henri; Valmier Jean; Leyris Jean-Philippe; Sonrier Corinne; Sokoloff Pierre; Philipson Yann; Schmitt Martine; Rognan Didier; Pin Jean-Philippe; Trinquet Eric; Charrier-Savournin FabienneNature communications (2018), 9 (1), 1042 ISSN:.Peripheral neuropathic pain (PNP) is a debilitating and intractable chronic disease, for which sensitization of somatosensory neurons present in dorsal root ganglia that project to the dorsal spinal cord is a key physiopathological process. Here, we show that hematopoietic cells present at the nerve injury site express the cytokine FL, the ligand of fms-like tyrosine kinase 3 receptor (FLT3). FLT3 activation by intra-sciatic nerve injection of FL is sufficient to produce pain hypersensitivity, activate PNP-associated gene expression and generate short-term and long-term sensitization of sensory neurons. Nerve injury-induced PNP symptoms and associated-molecular changes were strongly altered in Flt3-deficient mice or reversed after neuronal FLT3 downregulation in wild-type mice. A first-in-class FLT3 negative allosteric modulator, discovered by structure-based in silico screening, strongly reduced nerve injury-induced sensory hypersensitivity, but had no effect on nociception in non-injured animals. Collectively, our data suggest a new and specific therapeutic approach for PNP.
- 124Stone, R. M.; Manley, P. W.; Larson, R. A.; Capdeville, R. Midostaurin: its odyssey from discovery to approval for treating acute myeloid leukemia and advanced systemic mastocytosis. Blood Adv. 2018, 2, 444– 453, DOI: 10.1182/bloodadvances.2017011080[Crossref], [PubMed], [CAS], Google Scholar124https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXlsFOqtLs%253D&md5=2ce639598ecadae547e507f116704247Midostaurin: its odyssey from discovery to approval for treating acute myeloid leukemia and advanced systemic mastocytosisStone, Richard M.; Manley, Paul W.; Larson, Richard A.; Capdeville, RenaudBlood Advances (2018), 2 (4), 444-453CODEN: BALDBA; ISSN:2473-9537. (American Society of Hematology)A review. Midostaurin was a prototype kinase inhibitor, originally developed as a protein kinase C inhibitor and subsequently as an angiogenesis inhibitor, based on its inhibition of vascular endothelial growth factor receptor. Despite promising preclin. data, early clin. trials in multiple diseases showed only modest efficacy. In 1996, the relatively frequent occurrence of fms-like tyrosine kinase 3 (FLT3) activating mutations in acute myeloid leukemia (AML) was first recognized. Several years later, midostaurin was discovered to be a potent inhibitor of the FLT3 tyrosine kinase and to have activity against mutant forms of KIT proto-oncogene receptor tyrosine kinase, which drive advanced systemic mastocytosis (SM). Through a series of collaborations between industry and academia, midostaurin in combination with std. chemotherapy was evaluated in the Cancer and Leukemia Group B 10603/RATIFY study, a large, phase 3, randomized, placebo-controlled trial in patients with newly diagnosed FLT3-mutated AML. This was the first study to show significant improvements in overall survival and event-free survival with the addn. of a targeted therapy to std. chemotherapy in this population. Around the same time, durable responses were also obsd. in other trials of midostaurin in patients with advanced SM. Collectively, these clin. data led to the approval of midostaurin by the US Food and Drug Administration and the European Medicines Agency for both newly diagnosed FLT3-mutated AML and advanced SM.
- 125Gotlib, J.; Kluin-Nelemans, H. C.; George, T. I.; Akin, C.; Sotlar, K.; Hermine, O.; Awan, F. T.; Hexner, E.; Mauro, M. J.; Sternberg, D. W.; Villeneuve, M.; Huntsman Labed, A.; Stanek, E. J.; Hartmann, K.; Horny, H. P.; Valent, P.; Reiter, A. Efficacy and safety of midostaurin in advanced systemic mastocytosis. N. Engl. J. Med. 2016, 374, 2530– 2541, DOI: 10.1056/NEJMoa1513098[Crossref], [PubMed], [CAS], Google Scholar125https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvF2ksrvI&md5=c3b12f782bf5eec9fe84085d3809784bEfficacy and safety of midostaurin in advanced systemic mastocytosisGotlib, Jason; Kluin-Nelemans, Hanneke C.; George, Tracy I.; Akin, Cem; Sotlar, Karl; Hermine, Olivier; Awan, Farrukh T.; Hexner, Elizabeth; Mauro, Michael J.; Sternberg, David W.; Villeneuve, Matthieu; Labed, Alice Huntsman; Stanek, Eric J.; Hartmann, Karin; Horny, Hans-Peter; Valent, Peter; Reiter, AndreasNew England Journal of Medicine (2016), 374 (26), 2530-2541CODEN: NEJMAG; ISSN:1533-4406. (Massachusetts Medical Society)BACKGROUND: Advanced systemic mastocytosis comprises rare hematol. neoplasms that are assocd. with a poor prognosis and lack effective treatment options. The multikinase inhibitor midostaurin inhibits KIT D816V, a primary driver of disease pathogenesis. METHODS: We conducted an open-label study of oral midostaurin at a dose of 100 mg twice daily in 116 patients, of whom 89 with mastocytosis-related organ damage were eligible for inclusion in the primary efficacy population; 16 had aggressive systemic mastocytosis, 57 had systemic mastocytosis with an assocd. hematol. neoplasm, and 16 had mast-cell leukemia. The primary outcome was the best overall response. RESULTS: The overall response rate was 60% (95% confidence interval [CI], 49 to 70); 45% of the patients had a major response, which was defined as complete resoln. of at least one type of mastocytosis-related organ damage. Response rates were similar regardless of the subtype of advanced systemic mastocytosis, KIT mutation status, or exposure to previous therapy. The median best percentage changes in bone marrow mast-cell burden and serum tryptase level were -59% and -58%, resp. The median overall survival was 28.7 mo, and the median progression-free survival was 14.1 mo. Among the 16 patients with mast-cell leukemia, the median overall survival was 9.4 mo (95% CI, 7.5 to not estd.). Dose redn. owing to toxic effects occurred in 56% of the patients; re-escalation to the starting dose was feasible in 32% of those patients. The most frequent adverse events were low-grade nausea, vomiting, and diarrhea. New or worsening grade 3 or 4 neutropenia, anemia, and thrombocytopenia occurred in 24%, 41%, and 29% of the patients, resp., mostly in those with preexisting cytopenias. CONCLUSIONS: In this open-label study, midostaurin showed efficacy in patients with advanced systemic mastocytosis, including the highly fatal variant mast-cell leukemia.
- 126Campochiaro, P. A. Reduction of diabetic macular edema by oral administration of the kinase inhibitor PKC412. Invest. Ophthalmol. Visual Sci. 2004, 45, 922– 931, DOI: 10.1167/iovs.03-0955[Crossref], [PubMed], [CAS], Google Scholar126https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2c%252FpsFGrtw%253D%253D&md5=473379b2c21d18961353d37d9f0f54cbReduction of diabetic macular edema by oral administration of the kinase inhibitor PKC412Campochiaro Peter AInvestigative ophthalmology & visual science (2004), 45 (3), 922-31 ISSN:0146-0404.PURPOSE: To evaluate the efficacy and safety of PKC412, an orally administered kinase inhibitor, in subjects with diabetic macular edema. METHODS: This was a randomized (1:1:1:1), multicenter, double-masked, parallel-group study in which subjects (n = 141) received placebo or PKC412 (50, 100, or 150 mg/d) for up to 3 months. Subjects were 18 to 85 years of age and had retinal thickening that met predefined criteria and best corrected visual acuity of 55 letters or more. Efficacy was based on changes in retinal thickening measured by grading of fundus photographs and optical coherence tomography (OCT) and changes in visual acuity. RESULTS: Grading of fundus photographs showed a statistically significant decrease in the area of greatest retinal thickening in patients receiving 150 mg/d of PKC412 (P = 0.032). OCT demonstrated that the two higher doses of PKC412 caused a significant decrease in thickening in the region of greatest thickening and in the fovea (P < or = 039), with response in the high-dose group significantly different from that in the placebo group (difference = -66.69 micro m [95.2% CI: -128.57 to -4.81]; P = 0.030). Retinal volume for all locations also showed a significant decrease from baseline in the 100- and 150-mg/d PKC412 groups (P < or = 004), and the 150-mg/kg group showed significantly less retinal volume than the placebo group at 3 months (difference = -0.46 mm(3) [95.2% CI: -0.86-0.06]; P = 0.019). There was a small (4.36 letters), but significant (P = 0.007), improvement in visual acuity at 3 months compared with baseline in the 100-mg/d PKC412 group. Gastrointestinal side effects (diarrhea, nausea, and vomiting) were the most common adverse events attributed to the drug. Dose-related effects were observed for tolerability, glycemic control, and liver toxicity. CONCLUSIONS: Orally administered PKC412 at doses of 100 mg/d or higher may significantly reduce macular edema and improve visual acuity in diabetic subjects. However, concern regarding liver toxicity with systemic therapy makes local delivery an appealing approach.
- 127William, A. D.; Lee, A. C.; Poulsen, A.; Goh, K. C.; Madan, B.; Hart, S.; Tan, E.; Wang, H.; Nagaraj, H.; Chen, D.; Lee, C. P.; Sun, E. T.; Jayaraman, R.; Pasha, M. K.; Ethirajulu, K.; Wood, J. M.; Dymock, B. W. Discovery of the macrocycle (9E)-15-(2-(pyrrolidin-1-yl)ethoxy)-7,12,25-trioxa-19,21,24-triaza-tetracyclo[18. 3.1.1(2,5).1(14,18)]hexacosa-1(24),2,4,9,14(26),15,17,20,22-nonaene (SB1578), a potent inhibitor of janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) for the treatment of rheumatoid arthritis. J. Med. Chem. 2012, 55, 2623– 2640, DOI: 10.1021/jm201454n[ACS Full Text], [CAS], Google Scholar127https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XisFShsLY%253D&md5=efe684c2f2ff0b506d02c2ef911bfb2fDiscovery of the Macrocycle (9E)-15-(2-(Pyrrolidin-1-yl)ethoxy)-7,12,25-trioxa-19,21,24-triaza-tetracyclo[18.3.1.1(2,5).1(14,18)]hexacosa-1(24),2,4,9,14(26),15,17,20,22-nonaene (SB1578), a Potent Inhibitor of Janus Kinase 2/Fms-LikeTyrosine Kinase-3 (JAK2/FLT3) for the Treatment of Rheumatoid ArthritisWilliam, Anthony D.; Lee, Angeline C.-H.; Poulsen, Anders; Goh, Kee Chuan; Madan, Babita; Hart, Stefan; Tan, Evelyn; Wang, Haishan; Nagaraj, Harish; Chen, Dizhong; Lee, Chai Ping; Sun, Eric T.; Jayaraman, Ramesh; Pasha, Mohammad Khalid; Ethirajulu, Kantharaj; Wood, Jeanette M.; Dymock, Brian W.Journal of Medicinal Chemistry (2012), 55 (6), 2623-2640CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Herein, we describe the synthesis and SAR of a series of small mol. macrocycles that selectively inhibit JAK2 kinase within the JAK family and FLT3 kinase. Following a multiparameter optimization of a key aryl ring of the previously described SB1518 (pacritinib), the highly sol. 14l (I) was selected as the optimal compd. Oral efficacy in the murine collagen-induced arthritis (CIA) model for rheumatoid arthritis (RA) supported 14l as a potential treatment for autoimmune diseases and inflammatory disorders such as psoriasis and RA. Compd. 14l (SB1578) was progressed into development and is currently undergoing phase 1 clin. trials in healthy volunteers.
- 128Li, G. B.; Ma, S.; Yang, L. L.; Ji, S.; Fang, Z.; Zhang, G.; Wang, L. J.; Zhong, J. M.; Xiong, Y.; Wang, J. H.; Huang, S. Z.; Li, L. L.; Xiang, R.; Niu, D.; Chen, Y. C.; Yang, S. Y. Drug discovery against psoriasis: identification of a new potent Fms-like tyrosine kinase 3 (FLT3) inhibitor, 1-(4-((1H-pyrazolo[3,4-d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-3-(5-(tert-butyl)iso xazol-3-yl)urea, that showed potent activity in a psoriatic animal model. J. Med. Chem. 2016, 59, 8293– 8305, DOI: 10.1021/acs.jmedchem.6b00604[ACS Full Text], [CAS], Google Scholar128https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlOgt73L&md5=82b107175f8c3b7a2e1fc3e5db6d488eDrug Discovery against Psoriasis: Identification of a New Potent FMS-like Tyrosine Kinase 3 (FLT3) Inhibitor, 1-(4-((1H-Pyrazolo[3,4-d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-3-(5-(tert-butyl)isoxazol-3-yl)urea, That Showed Potent Activity in a Psoriatic Animal ModelLi, Guo-Bo; Ma, Shuang; Yang, Ling-Ling; Ji, Sen; Fang, Zhen; Zhang, Guo; Wang, Li-Jiao; Zhong, Jie-Min; Xiong, Yu; Wang, Jiang-Hong; Huang, Shen-Zhen; Li, Lin-Li; Xiang, Rong; Niu, Dawen; Chen, Ying-Chun; Yang, Sheng-YongJournal of Medicinal Chemistry (2016), 59 (18), 8293-8305CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Psoriasis is a chronic T-cell-mediated autoimmune disease, and FMS-like tyrosine kinase 3 (FLT3) has been considered as a potential mol. target for the treatment of psoriasis. In this investigation, structural optimization was performed on a lead compd., 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)phenyl)-3-(4-chloro-3- (trifluoromethyl)phenyl)urea, which showed a moderate inhibitory activity against FLT3. A series of pyrazolo[3,4-d]pyrimidine derivs. were synthesized, and structure-activity relationship anal. led to the discovery of a no. of potent FLT3 inhibitors. One of the most active compds., 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(5-tert-butylisoxazol-3-yl)urea (I), was then chosen for in-depth anti-psoriasis studies because this compd. displayed the highest potency in a preliminary anti-psoriasis test. Compd. I exhibited significant anti-psoriatic effects in the K14-VEGF transgenic mouse model of psoriasis, and no recurrence was found 15 days later after the last administration. Detailed mechanisms of action of compd. I were also investigated. Collectively, compd. I could be a potential drug candidate for psoriasis treatment.
- 129Yang, L. L.; Li, G. B.; Ma, S.; Zou, C.; Zhou, S.; Sun, Q. Z.; Cheng, C.; Chen, X.; Wang, L. J.; Feng, S.; Li, L. L.; Yang, S. Y. Structure-activity relationship studies of pyrazolo[3,4-d]pyrimidine derivatives leading to the discovery of a novel multikinase inhibitor that potently inhibits FLT3 and VEGFR2 and evaluation of its activity against acute myeloid leukemia in vitro and in vivo. J. Med. Chem. 2013, 56, 1641– 1655, DOI: 10.1021/jm301537p[ACS Full Text], [CAS], Google Scholar129https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvVCjtbs%253D&md5=49142fb4b7dfa62310b090ed073b490fStructure-Activity Relationship Studies of Pyrazolo[3,4-d]pyrimidine Derivatives Leading to the Discovery of a Novel Multikinase Inhibitor That Potently Inhibits FLT3 and VEGFR2 and Evaluation of Its Activity against Acute Myeloid Leukemia in Vitro and in VivoYang, Ling-Ling; Li, Guo-Bo; Ma, Shuang; Zou, Chan; Zhou, Shu; Sun, Qi-Zheng; Cheng, Chuan; Chen, Xin; Wang, Li-Jiao; Feng, Shan; Li, Lin-Li; Yang, Sheng-YongJournal of Medicinal Chemistry (2013), 56 (4), 1641-1655CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Pyrazolopyrimidinyloxyphenyl ureas such as I were prepd. as inhibitors of the kinases Flt3 and VEGFR2 for potential use as antitumor agents. Structural modification of an initial pyrazolopyrimidinyloxyphenyl urea lead compd. and detn. of the relationships of Flt3 inhibition, inhibition of proliferation, and inhibition of angiogenesis in human acute myeloid leukemia (AML) cells and in transgenic-zebrafish to the structure of pyrazolopyrimidinyloxyphenyl ureas led to the discovery of I. I was a multikinase inhibitor that potently inhibited both FLT3 (IC50 = 39 nM) and VEGFR2 (IC50 = 12 nM). In an AML xenograft mouse model, a once-daily dose of I at 10 mg/kg for 18 days led to complete tumor regression without obvious toxicity; the mechanism of action of I was studied.
- 130Yan, H. X.; Li, W. W.; Zhang, Y.; Wei, X. W.; Fu, L. X.; Shen, G. B.; Yin, T.; Li, X. Y.; Shi, H. S.; Wan, Y.; Zhang, Q. Y.; Li, J.; Yang, S. Y.; Wei, Y. Q. Accumulation of FLT3(+) CD11c (+) dendritic cells in psoriatic lesions and the anti-psoriatic effect of a selective FLT3 inhibitor. Immunol. Res. 2014, 60, 112– 126, DOI: 10.1007/s12026-014-8521-4[Crossref], [PubMed], [CAS], Google Scholar130https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXpsFelt7g%253D&md5=cccc42ce83e27f8d222d9f3087481a1aAccumulation of FLT3+ CD11c+ dendritic cells in psoriatic lesions and the anti-psoriatic effect of a selective FLT3 inhibitorYan, Heng-Xiu; Li, Wei-Wei; Zhang, Yan; Wei, Xia-Wei; Fu, Li-Xin; Shen, Guo-Bo; Yin, Tao; Li, Xiu-Ying; Shi, Hua-Shan; Wan, Yang; Zhang, Qing-Yin; Li, Jiong; Yang, Sheng-Yong; Wei, Yu-QuanImmunologic Research (2014), 60 (1), 112-126CODEN: IMRSEB; ISSN:0257-277X. (Springer)Psoriasis is a common chronic T-cell-mediated autoimmune skin disease, and traditional immunotherapies for psoriasis have focused on the direct inhibition of T cells, which often causes toxicity and lacks long-term effectiveness. Safe and effective therapeutic strategies are strongly needed for psoriasis. In this study, we show for the first time a significant accumulation of FLT3+ CD11c+ dendritic cells (DCs) in human psoriatic lesions and in the skin of exptl. preclin. K14-VEGF transgenic homozygous mice, our animal model, although not an exact match for human psoriasis, displays many characteristics of inflammatory skin inflammation. SKLB4771, a potent and selective FLT3 inhibitor that we designed and synthesized, was used to treat cutaneous inflammation and psoriasis-like symptoms of disease in mice and almost completely cured the psoriasis-like disease without obvious toxicity. Mechanistic studies indicated that SKLB4771 treatment significantly decreased the no. and activation of pDCs and mDCs in vitro and in vivo, and subsequent T-cell cascade reactions mediated by Th1/Th17 pathways. These findings show that targeted inhibition of FLT3, and hence direct interference with DCs, may be a novel therapeutic approach for the treatment of psoriasis.
- 131Ichijo, H.; Nishida, E.; Irie, K.; Ten Dijke, P.; Saitoh, M.; Moriguchi, T.; Takagi, M.; Matsumoto, K.; Miyazono, K.; Gotoh, Y. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science 1997, 275, 90– 94, DOI: 10.1126/science.275.5296.90[Crossref], [PubMed], [CAS], Google Scholar131https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXjsFSmtQ%253D%253D&md5=c848d137cce82c79a75a21efb217feaeInduction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathwaysIchijo, Hidenori; Nishida, Eisuke; Irie, Kenji; ten Dijke, Peter; Saitoh, Masao; Moriguchi, Tetsuo; Takagi, Minoru; Matsumoto, Kunihiro; Miyazono, Kohei; Gotoh, YukihoScience (Washington, D. C.) (1997), 275 (5296), 90-94CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Mitogen-activated protein (MAP) kinase cascades are activated in response to various extracellular stimuli, including growth factors and environmental stresses. A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, resp. Overexpression of ASK1 induced apoptotic cell death, and ASK1 was activated in cells treated with tumor necrosis factor-α (TNF-α). Moreover, TNF-α-induced apoptosis was inhibited by a catalytically inactive form of ASK1. ASK1 may be a key element in the mechanism of stress- and cytokine-induced apoptosis.
- 132Baig, M. H.; Baker, A.; Ashraf, G. M.; Dong, J. J. ASK1 and its role in cardiovascular and other disorders: available treatments and future prospects. Expert Rev. Proteomics 2019, 16, 857– 870, DOI: 10.1080/14789450.2019.1676735[Crossref], [PubMed], [CAS], Google Scholar132https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFyhtbbO&md5=cd18d7b2840b4f7c16611e94e93d1984ASK1 and its role in cardiovascular and other disorders: available treatments and future prospectsBaig, Mohammad Hassan; Baker, Abu; Ashraf, Ghulam M.; Dong, Jae-JuneExpert Review of Proteomics (2019), 16 (10), 857-870CODEN: ERPXA3; ISSN:1478-9450. (Taylor & Francis Ltd.)A review. Apoptosis signal-regulating kinase 1 (ASK1), also known as MAP3K5, is a member of mitogen-activated protein kinase kinase kinase (MAP3K) family and is well reported as crucial in the regulation of the JNK and P38 pathways. ASK1 is activated in response to a diverse array of stresses such as endoplasmic reticulum stress, lipopolysaccharides, tumor necrosis factor alpha, and reactive oxygen species. The activation of ASK1 induces various stress responses.: Considering ASK1 as an important therapeutic drug target, here we have discussed the role of ASK1 in the progression of various diseases. We have also provided an overview of the available inhibitors for ASK1. The success of computational-based approaches toward ASK1 inhibitor design has also been discussed.: A no. of reports have outlined the prominent role of ASK1 in the pathogenesis of several diseases. The discovery of novel ASK1 inhibitors would have a wide range of applications in medical science. In-silico techniques have been successfully used in the design of some novel ASK1 inhibitors. The use of machine learning-based approaches in combination with structure-based virtual screening (SBVS) and ligand-based virtual screening (LBVS) will be helpful toward the development of potent ASK1 inhibitors.
- 133Fujisawa, T. Therapeutic application of apoptosis signal-regulating kinase 1 inhibitors. Adv. Biol. Regul 2017, 66, 85– 90, DOI: 10.1016/j.jbior.2017.10.004[Crossref], [PubMed], [CAS], Google Scholar133https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs12rur7N&md5=91ed7baecfcf9fb42c0437fa8ebbf87aTherapeutic application of apoptosis signal-regulating kinase 1 inhibitorsFujisawa, TakaoAdvances in Biological Regulation (2017), 66 (), 85-90CODEN: ABRDE5; ISSN:2212-4934. (Elsevier Ltd.)A review. Apoptosis signal-regulating kinase 1 (ASK1) is a member of the stress-activated mitogen-activated protein kinase kinase kinase (MAP3K) family. ASK1 is an attractive drug target, owing to its essential role in a wide variety of human diseases including neurodegenerative disorders, inflammatory diseases and cancer. Recent studies have suggested that pharmacol. manipulations using small mol. ASK1 inhibitors may be beneficial in exptl. human disease models. In this review, we highlight the current understanding of ASK1 inhibitors as a potential therapy for human diseases.
- 134Kawarazaki, Y.; Ichijo, H.; Naguro, I. Apoptosis signal-regulating kinase 1 as a therapeutic target. Expert Opin. Ther. Targets 2014, 18, 651– 664, DOI: 10.1517/14728222.2014.896903[Crossref], [PubMed], [CAS], Google Scholar134https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXotlWgsr8%253D&md5=85423452f6b9e36c4b62986b5c086081Apoptosis signal-regulating kinase 1 as a therapeutic targetKawarazaki, Yosuke; Ichijo, Hidenori; Naguro, IsaoExpert Opinion on Therapeutic Targets (2014), 18 (6), 651-664CODEN: EOTTAO; ISSN:1472-8222. (Informa Healthcare)A review. Introduction: All organisms are ordinarily exposed to various stresses. It is important for organisms to possess appropriate stress response mechanisms and to maintain homeostasis because the disruption of a stress response system can cause various diseases. Apoptosis signal-regulating kinase 1 (ASK1) is one of the stress-responsive MAP3Ks. ASK1 plays an important role in the response to reactive oxygen species (ROS), endoplasmic reticulum stress and pro-inflammatory cytokines, and it is involved in the pathogenesis of various diseases. Areas covered: In this review, the authors describe recent literature concerning the intricate and elaborate regulation system of ASK1, the function of ASK1 during a cellular stress response and the involvement of ASK1 in many diseases, including cancer, neurodegenerative diseases, infections, diabetes and cardiovascular diseases. Expert opinion: In certain disease conditions, ASK1 plays a protective role, whereas ASK1 can exacerbate the pathol. of other diseases. Although ASK1 is involved in various diseases, there is no therapy or drug that targets ASK1 for use in a clin. setting. Recently, ASK1 inhibitors (K811 and MSC2032964A) have emerged, and their therapeutic potentials have been tested in vivo. ASK1 is currently receiving considerable attention as a new therapeutic target.
- 135Loomba, R.; Lawitz, E.; Mantry, P. S.; Jayakumar, S.; Caldwell, S. H.; Arnold, H.; Diehl, A. M.; Djedjos, C. S.; Han, L.; Myers, R. P.; Subramanian, G. M.; McHutchison, J. G.; Goodman, Z. D.; Afdhal, N. H.; Charlton, M. R. Investigators, GS-US-384–1497. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial. Hepatology 2018, 67, 549– 559, DOI: 10.1002/hep.29514[Crossref], [PubMed], [CAS], Google Scholar135https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsFKjtbs%253D&md5=ca04f9bbc0b7d65c2b4493d479c2d751The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trialLoomba, Rohit; Lawitz, Eric; Mantry, Parvez S.; Jayakumar, Saumya; Caldwell, Stephen H.; Arnold, Hays; Diehl, Anna Mae; Djedjos, C. Stephen; Han, Ling; Myers, Robert P.; Subramanian, G. Mani; McHutchison, John G.; Goodman, Zachary D.; Afdhal, Nezam H.; Charlton, Michael R.Hepatology (Hoboken, NJ, United States) (2018), 67 (2), 549-559CODEN: HPTLD9; ISSN:0270-9139. (John Wiley & Sons, Inc.)Inhibition of apoptosis signal-regulating kinase 1, a serine/threonine kinase, leads to improvement in inflammation and fibrosis in animal models of nonalcoholic steatohepatitis. We evaluated the safety and efficacy of selonsertib, a selective inhibitor of apoptosis signal-regulating kinase 1, alone or in combination with simtuzumab, in patients with nonalcoholic steatohepatitis and stage 2 or 3 liver fibrosis. In this multicenter phase 2 trial, 72 patients were randomized to receive 24 wk of open-label treatment with either 6 or 18 mg of selonsertib orally once daily with or without once-weekly injections of 125 mg of simtuzumab or simtuzumab alone. The effect of treatment was assessed by paired pretreatment and posttreatment liver biopsies, magnetic resonance elastog., magnetic resonance imaging-estd. proton d. fat fraction, quant. collagen content, and noninvasive markers of liver injury. Due to the lack of effect of simtuzumab on histol. or selonsertib pharmacokinetics, selonsertib groups with and without simtuzumab were pooled. After 24 wk of treatment, the proportion of patients with a one or more stage redn. in fibrosis in the 18-mg selonsertib group was 13 of 30 (43%; 95% confidence interval, 26-63); in the 6-mg selonsertib group, 8 of 27 (30%; 95% confidence interval, 14-50); and in the simtuzumab-alone group, 2 of 10 (20%; 95% confidence interval, 3-56). Improvement in fibrosis was assocd. with redns. in liver stiffness on magnetic resonance elastog., collagen content and lobular inflammation on liver biopsy, as well as improvements in serum biomarkers of apoptosis and necrosis. There were no significant differences in adverse events between the treatment groups. Conclusion: These findings suggest that selonsertib may reduce liver fibrosis in patients with nonalcoholic steatohepatitis and stage 2-3 fibrosis. (Hepatol. 2018;67:549-559).
- 136Harrison, S. A.; Wong, V. W.; Okanoue, T.; Bzowej, N.; Vuppalanchi, R.; Younes, Z.; Kohli, A.; Sarin, S.; Caldwell, S. H.; Alkhouri, N.; Shiffman, M. L.; Camargo, M.; Li, G.; Kersey, K.; Jia, C.; Zhu, Y.; Djedjos, C. S.; Subramanian, G. M.; Myers, R. P.; Gunn, N.; Sheikh, A.; Anstee, Q. M.; Romero-Gomez, M.; Trauner, M.; Goodman, Z.; Lawitz, E. J.; Younossi, Z. Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: Results from randomized phase III STELLAR trials. J. Hepatol. 2020, 73, 26– 39, DOI: 10.1016/j.jhep.2020.02.027[Crossref], [PubMed], [CAS], Google Scholar136https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXlvFGks7o%253D&md5=a7b9e9142c45ab137a849b7b3a8e6c38Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: Results from randomized phase III STELLAR trialsHarrison, Stephen A.; Wong, Vincent Wai-Sun; Okanoue, Takeshi; Bzowej, Natalie; Vuppalanchi, Raj; Younes, Ziad; Kohli, Anita; Sarin, Shiv; Caldwell, Stephen H.; Alkhouri, Naim; Shiffman, Mitchell L.; Camargo, Marianne; Li, Georgia; Kersey, Kathryn; Jia, Catherine; Zhu, Yanni; Djedjos, C. Stephen; Subramanian, G. Mani; Myers, Robert P.; Gunn, Nadege; Sheikh, Aasim; Anstee, Quentin M.; Romero-Gomez, Manuel; Trauner, Michael; Goodman, Zachary; Lawitz, Eric J.; Younossi, ZobairJournal of Hepatology (2020), 73 (1), 26-39CODEN: JOHEEC; ISSN:0168-8278. (Elsevier B.V.)Apoptosis signal-regulating kinase 1 (ASK1) plays a key role in hepatocyte injury, inflammation, and fibrosis in non-alc. steatohepatitis (NASH). We evaluated the safety and antifibrotic effect of selonsertib, a selective inhibitor of ASK1, in patients with advanced fibrosis due to NASH.We conducted 2 randomized, double-blind, placebo-controlled, phase III trials of selonsertib in patients with NASH and bridging fibrosis (F3, STELLAR-3) or compensated cirrhosis (F4, STELLAR-4). Patients were randomized 2:2:1 to receive selonsertib 18 mg, selonsertib 6 mg, or placebo once daily for 48 wk. Liver biopsies were performed at screening and week 48 and non-invasive tests of fibrosis (NITs) were evaluated. The primary efficacy endpoint was the proportion of patients with ≥1-stage improvement in fibrosis without worsening of NASH at week 48. Addnl. endpoints included changes in NITs, progression to cirrhosis (in STELLAR-3), and liver-related clin. events.Neither trial met the primary efficacy endpoint. In STELLAR-3, fibrosis improvement without worsening of NASH was obsd. in 10% (31/322, p = 0.49 vs. placebo), 12% (39/321, p = 0.93 vs. placebo), and 13% (21/159) of patients in the selonsertib 18 mg, selonsertib 6 mg, and placebo groups, resp. In STELLAR-4, the primary endpoint was achieved in 14% (51/354; p = 0.56), 13% (45/351; p = 0.93), and 13% (22/172) of patients, resp. Although selonsertib led to dose-dependent redns. in hepatic phospho-p38 expression indicative of pharmacodynamic activity, it had no significant effect on liver biochem., NITs, progression to cirrhosis, or adjudicated clin. events. The rates and types of adverse events were similar among selonsertib and placebo groups.Forty-eight weeks of selonsertib monotherapy had no antifibrotic effect in patients with bridging fibrosis or compensated cirrhosis due to NASH.Patients with non-alc. steatohepatitis (NASH) can develop scarring of the liver (fibrosis), including cirrhosis, which increases the risks of liver failure and liver cancer. We tested whether 48 wk of treatment with selonsertib reduced fibrosis in patients with NASH and advanced liver scarring. We did not find that selonsertib reduced fibrosis in these patients.Clinicaltrials.gov nos. NCT03053050 and NCT03053063.
- 137Chertow, G. M.; Pergola, P. E.; Chen, F.; Kirby, B. J.; Sundy, J. S.; Patel, U. D. Effects of selonsertib in patients with diabetic kidney disease. J. Am. Soc. Nephrol. 2019, 30, 1980– 1990, DOI: 10.1681/ASN.2018121231[Crossref], [PubMed], [CAS], Google Scholar137https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXnsFGqu78%253D&md5=3387b2e69941bfac54796a36528e1f4cEffects of selonsertib in patients with diabetic kidney diseaseChertow, Glenn M.; Pergola, Pablo E.; Chen, Fang; Kirby, Brian J.; Sundy, John S.; Pate, Uptal D.Journal of the American Society of Nephrology (2019), 30 (10), 1980-1990CODEN: JASNEU; ISSN:1046-6673. (American Society of Nephrology)Background Apoptosis signal-regulating kinase 1 (ASK1) activation in glomerular and tubular cells result- ing from oxidative stress may drive kidney disease progression. Findings in animal models identified selonsertib, a selective ASK1 inhibitor, as a potential therapeutic agent. Methods In a phase 2 trial evaluating selonsertib's safety and efficacy in adults with type 2 diabetes and treatment-refractory moderate-to-advanced diabetic kidney disease, we randomly assigned 333 adults in a 1:1:1:1 allocation to selonsertib (oral daily doses of 2, 6, or 18 mg) or placebo. Primary outcome was change from baseline eGFR at 48 wk. Results Selonsertib appeared safe, with no dose-dependent adverse effects over 48 wk. Although mean eGFR for selonsertib and placebo groups did not differ significantly at 48 wk, acute effects related to inhibition of creatinine secretion by selonsertib confounded eGFR differences at 48 wk. Because of this unanticipated effect, we used piecewise linear regression, finding two dose-dependent effects: an acute and more pronounced eGFR decline from 0 to 4 wk (creatinine secretion effect) and an attenuated eGFR decline between 4 and 48 wk (therapeutic effect) with higher doses of selonsertib. A post hoc anal. (excluding data for 20 patients from two sites with Good Clin. Practice compliance- related issues) found that between 4 and 48 wk, rate of eGFR decline was reduced 71% for the 18-mg group relative to placebo (difference 3.11±1.53 mL/min per 1.73 m2 annualized over 1 yr; 95% confi- dence interval, 0.10-6.13; nominal P=0.043). Effects on urine albumin-to-creatinine ratio did not differ between selonsertib and placebo. Conclusions Although the trial did not meet its primary endpoint, exploratory post hoc analyses suggest that selonsertib may slow diabetic kidney disease progression.
- 138Anstee, Q. M.; Lawitz, E. J.; Alkhouri, N.; Wong, V. W.; Romero-Gomez, M.; Okanoue, T.; Trauner, M.; Kersey, K.; Li, G.; Han, L.; Jia, C.; Wang, L.; Chen, G.; Subramanian, G. M.; Myers, R. P.; Djedjos, C. S.; Kohli, A.; Bzowej, N.; Younes, Z.; Sarin, S.; Shiffman, M. L.; Harrison, S. A.; Afdhal, N. H.; Goodman, Z.; Younossi, Z. M. Noninvasive tests accurately identify advanced fibrosis due to NASH: baseline data from the STELLAR trials. Hepatology 2019, 70, 1521– 1530, DOI: 10.1002/hep.30842[Crossref], [PubMed], [CAS], Google Scholar138https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3MzjvFOlsw%253D%253D&md5=81adfb1725cdaa92816f9e43155d9a17Noninvasive Tests Accurately Identify Advanced Fibrosis due to NASH: Baseline Data From the STELLAR TrialsAnstee Quentin M; Anstee Quentin M; Lawitz Eric J; Alkhouri Naim; Wong Vincent Wai-Sun; Romero-Gomez Manuel; Okanoue Takeshi; Trauner Michael; Kersey Kathryn; Li Georgia; Han Ling; Jia Catherine; Wang Lulu; Chen Guang; Subramanian G Mani; Myers Robert P; Djedjos C Stephen; Kohli Anita; Bzowej Natalie; Younes Ziad; Sarin Shiv; Shiffman Mitchell L; Harrison Stephen A; Afdhal Nezam H; Goodman Zachary; Younossi Zobair MHepatology (Baltimore, Md.) (2019), 70 (5), 1521-1530 ISSN:.Accurate noninvasive tests (NITs) are needed to replace liver biopsy for identifying advanced fibrosis caused by nonalcoholic steatohepatitis (NASH). We analyzed screening data from two phase 3 trials of selonsertib to assess the ability of NITs to discriminate advanced fibrosis. Centrally read biopsies from the STELLAR studies, which enrolled patients with bridging fibrosis and compensated cirrhosis, were staged according to the NASH Clinical Research Network classification. We explored associations between fibrosis stage and NITs, including the nonalcoholic fatty liver disease fibrosis score (NFS), fibrosis-4 (FIB-4) index, Enhanced Liver Fibrosis (ELF) test, and liver stiffness by vibration-controlled transient elastography (LS by VCTE). The performance of these tests to discriminate advanced fibrosis, either alone or in combinations, was evaluated using areas under the receiver operating characteristic curve (AUROCs) with 5-fold cross-validation repeated 100 times. Of the 4,404 patients screened for these trials, 3,202 had evaluable biopsy data: 940 with F0-F2 fibrosis and 2,262 with F3-F4 fibrosis. Significant differences between median values of NITs for patients with F0-F2 versus F3-F4 fibrosis were observed: -0.972 versus 0.318 for NFS, 1.18 versus 2.20 for FIB-4, 9.22 versus 10.39 for ELF, and 8.8 versus 16.5 kPa for LS by VCTE (all P < 0.001). AUROCs ranged from 0.75 to 0.80 to discriminate advanced fibrosis. FIB-4 followed by an LS by VCTE or ELF test in those with indeterminate values (FIB-4 between 1.3 and 2.67) maintained an acceptable performance while reducing the rate of indeterminate results. Conclusion: Among patients being considered for enrollment into clinical trials, NITs alone or in combination can reduce the need for liver biopsy to discriminate advanced fibrosis caused by NASH. The predictive value of these tests for general screening will require confirmation in a real-world population.
- 139Lanier, M.; Pickens, J.; Bigi, S. V.; Bradshaw-Pierce, E. L.; Chambers, A.; Cheruvallath, Z. S.; Cole, D.; Dougan, D. R.; Ermolieff, J.; Gibson, T.; Halkowycz, P.; Hirokawa, A.; Ivetac, A.; McBride, C.; Miura, J.; Nunez, E.; Sabat, M.; Tyhonas, J.; Wang, H. X.; Wang, X. L.; Swann, S. Structure-based design of ASK1 inhibitors as potential agents for heart failure. ACS Med. Chem. Lett. 2017, 8, 1341– 1341, DOI: 10.1021/acsmedchemlett.7b00457[ACS Full Text], [CAS], Google Scholar139https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslOmsL%252FP&md5=ba3724601624b9af4ffa26ab9b266f35Correction to "Structure-Based Design of ASK1 Inhibitors as Potential Agents for Heart Failure" [Erratum to document cited in CA166:413694]Lanier, Marion; Pickens, Jason; Bigi, Simone V.; Bradshaw-Pierce, Erica L.; Chambers, Alison; Cheruvallath, Zacharia S.; Cole, Derek; Dougan, Douglas R.; Ermolieff, Jacques; Gibson, Tony; Halkowycz, Petro; Hirokawa, Aki; Ivetac, Anthony; Miura, Joanne; Nunez, Evan; Sabat, Mark; Tyhonas, John; Wang, Haixia; Wang, Xiaolun; Swann, SteveACS Medicinal Chemistry Letters (2017), 8 (12), 1341CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)In the original publication, author Chris McBride was omitted from the author list; the correction is provided here.
- 140Himmelbauer, M. K.; Xin, Z. L.; Jones, J. H.; Enyedy, I.; King, K.; Marcotte, D. J.; Murugan, P.; Santoro, J. C.; Hesson, T.; Spilker, K.; Johnson, J. L.; Luzzio, M. J.; Gilfillan, R.; de Turiso, F. G. L. Rational design and optimization of a novel class of macrocyclic apoptosis signal-regulating kinase 1 inhibitors. J. Med. Chem. 2019, 62, 10740– 10756, DOI: 10.1021/acs.jmedchem.9b01206[ACS Full Text], [CAS], Google Scholar140https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitFeqsrnL&md5=bceb203a92c314a775b1d8d116cafcadRational Design and Optimization of a Novel Class of Macrocyclic Apoptosis Signal-Regulating Kinase 1 InhibitorsHimmelbauer, Martin K.; Xin, Zhili; Jones, J. Howard; Enyedy, Istvan; King, Kristopher; Marcotte, Douglas J.; Murugan, Paramasivam; Santoro, Joseph C.; Hesson, Thomas; Spilker, Kerri; Johnson, Joshua L.; Luzzio, Michael J.; Gilfillan, Rab; de Turiso, Felix Gonzalez-LopezJournal of Medicinal Chemistry (2019), 62 (23), 10740-10756CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Structural anal. of a known ASK1 inhibitor bound to its kinase domain led to the design and synthesis of the novel macrocyclic inhibitor I (cell IC50 = 1.2μM). The profile of this compd. was optimized for CNS penetration following two independent strategies: a rational design approach leading to II and a parallel synthesis approach leading to III. Both analogs are potent ASK1 inhibitors in biochem. and cellular assays (II, cell IC50 = 95 nM; III, cell IC50 = 123 nM) and have moderate to low efflux ratio (ER) in an MDR1-MDCK assay (II, ER = 5.2; III, ER = 1.5). In vivo PK studies revealed that inhibitor II had moderate CNS penetration (Kp,uu = 0.17) and analog III had high CNS penetration (Kp,uu = 1.0).
- 141Guo, X.; Harada, C.; Namekata, K.; Matsuzawa, A.; Camps, M.; Ji, H.; Swinnen, D.; Jorand-Lebrun, C.; Muzerelle, M.; Vitte, P. A.; Ruckle, T.; Kimura, A.; Kohyama, K.; Matsumoto, Y.; Ichijo, H.; Harada, T. Regulation of the severity of neuroinflammation and demyelination by TLR-ASK1-p38 pathway. EMBO Mol. Med. 2010, 2, 504– 515, DOI: 10.1002/emmm.201000103[Crossref], [PubMed], [CAS], Google Scholar141https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXosFeiuw%253D%253D&md5=f164a951b512af060b05b2906cbad96eRegulation of the severity of neuroinflammation and demyelination by TLR-ASK1-p38 pathwayGuo, Xiaoli; Harada, Chikako; Namekata, Kazuhiko; Matsuzawa, Atsushi; Camps, Monsterrat; Ji, Hong; Swinnen, Dominique; Jorand-Lebrun, Catherine; Muzerelle, Mathilde; Vitte, Pierre-Alain; Ruckle, Thomas; Kimura, Atsuko; Kohyama, Kuniko; Matsumoto, Yoh; Ichijo, Hidenori; Harada, TakayukiEMBO Molecular Medicine (2010), 2 (12), 504-515CODEN: EMMMAM; ISSN:1757-4684. (Wiley-Blackwell)Apoptosis signal-regulating kinase 1 (ASK1) is an evolutionarily conserved mitogen-activated protein kinase (MAPK) kinase kinase which plays important roles in stress and immune responses. Here, we show that ASK1 deficiency attenuates neuroinflammation in exptl. autoimmune encephalomyelitis (EAE), without affecting the proliferation capability of T cells. Moreover, we found that EAE upregulates expression of Toll-like receptors (TLRs) in activated astrocytes and microglia, and that TLRs can synergize with ASK1-p38 MAPK signalling in the release of key chemokines from astrocytes. Consequently, oral treatment with a specific small mol. wt. inhibitor of ASK1 suppressed EAE-induced autoimmune inflammation in both spinal cords and optic nerves. These results suggest that the TLR-ASK1-p38 pathway in glial cells may serve as a valid therapeutic target for autoimmune demyelinating disorders including multiple sclerosis.
- 142Fujisawa, T.; Takahashi, M.; Tsukamoto, Y.; Yamaguchi, N.; Nakoji, M.; Endo, M.; Kodaira, H.; Hayashi, Y.; Nishitoh, H.; Naguro, I.; Homma, K.; Ichijo, H. The ASK1-specific inhibitors K811 and K812 prolong survival in a mouse model of amyotrophic lateral sclerosis. Hum. Mol. Genet. 2016, 25, 245– 253, DOI: 10.1093/hmg/ddv467[Crossref], [PubMed], [CAS], Google Scholar142https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtF2ltbvP&md5=cfa4702fbeed701f7e2640e3cb7931deThe ASK1-specific inhibitors K811 and K812 prolong survival in a mouse model of amyotrophic lateral sclerosisFujisawa, Takao; Takahashi, Motoo; Tsukamoto, Yuka; Yamaguchi, Namiko; Nakoji, Masayoshi; Endo, Megumi; Kodaira, Hiroshi; Hayashi, Yuki; Nishitoh, Hideki; Naguro, Isao; Homma, Kengo; Ichijo, HidenoriHuman Molecular Genetics (2016), 25 (2), 245-253CODEN: HMGEE5; ISSN:0964-6906. (Oxford University Press)Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no cure. To develop effective treatments for this devastating disease, an appropriate strategy for targeting the mol. responsible for the pathogenesis of ALS is needed. We previously reported that mutant SOD1 protein causes motor neuron death through activation of ASK1, a mitogen-activated protein kinase kinase kinase. Addnl., we recently developed K811 (I) and K812 (II), which are selective inhibitors for ASK1. Here, we report the effect of K811 and K812 in a mouse model of ALS (SOD1G93A transgenic mice). Oral administration of K811 or K812 significantly extended the life span of SOD1G93A transgenic mice (1.06 and 1.08% improvement in survival). Moreover, ASK1 activation obsd. in the lumbar spinal cord of mice at the disease progression stage was markedly decreased in the K811- and K812-treated groups. In parallel, immunohistochem. anal. revealed that K811 and K812 treatment inhibited glial activation in the lumbar spinal cord of SOD1G93A transgenic mice. These results reinforce the importance of ASK1 as a therapeutic target for ALS treatment.
- 143Budas, G. R.; Boehm, M.; Kojonazarov, B.; Viswanathan, G.; Tian, X.; Veeroju, S.; Novoyatleva, T.; Grimminger, F.; Hinojosa-Kirschenbaum, F.; Ghofrani, H. A.; Weissmann, N.; Seeger, W.; Liles, J. T.; Schermuly, R. T. Ask1 inhibition halts disease progression in preclinical models of pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 2018, 197, 373– 385, DOI: 10.1164/rccm.201703-0502OC[Crossref], [PubMed], [CAS], Google Scholar143https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitFKks77N&md5=7a4d24e0cff8fb71b778c66cb954a7abASK1 inhibition halts disease progression in preclinical models of pulmonary arterial hypertensionBudas, Grant R.; Boehm, Mario; Kojonazarov, Baktybek; Viswanathan, Gayathri; Tian, Xia; Veeroju, Swathi; Novoyatleva, Tatyana; Grimminger, Friedrich; Hinojosa-Kirschenbaum, Ford; Ghofrani, Hossein A.; Weissmann, Norbert; Seeger, Werner; Liles, John T.; Schermuly, Ralph T.American Journal of Respiratory and Critical Care Medicine (2018), 197 (3), 373-385CODEN: AJCMED; ISSN:1073-449X. (American Thoracic Society)Rationale: Progression of pulmonary arterial hypertension (PAH) is assocd. with pathol. remodeling of the pulmonary vasculature and the right ventricle (RV). Oxidative stress drives the remodeling process through activation of MAPKs (mitogen-activated protein kinases), which stimulate apoptosis, inflammation, and fibrosis. Objectives: We investigated whether pharmacol. inhibition of the redox-sensitive apical MAPK, ASK1 (apoptosis signal-regulating kinase 1), can halt the progression of pulmonary vascular and RV remodeling. Methods: A selective, orally available ASK1 inhibitor, GS-444217, was administered to two preclin. rat models of PAH (monocrotaline and Sugen/hypoxia), a murine model of RV pressure overload induced by pulmonary artery banding, and cellular models. Measurements and Main Results: Oral administration of GS- 444217 dose dependently reduced pulmonary arterial pressure and reduced RV hypertrophy in PAH models. The therapeutic efficacy of GS-444217 was assocd. with reduced ASK1 phosphorylation, reduced muscularization of the pulmonary arteries, and reduced fibrotic gene expression in the RV. Importantly, efficacy was obsd. when GS-444217 was administered to animals with established disease and also directly reduced cardiac fibrosis and improved cardiac function in a model of isolated RV pressure overload. In cellular models, GS-444217 reduced phosphorylation of p38 and JNK (c-Jun N-terminal kinase) induced by adenoviral overexpression of ASK1 in rat cardiomyocytes and reduced activation/migration of primary mouse cardiac fibroblasts and human pulmonary adventitial fibroblasts derived from patients with PAH. Conclusions: ASK1 inhibition reduced pathol. remodeling of the pulmonary vasculature and the right ventricle and halted progression of pulmonary hypertension in rodent models. These preclin. data inform the first description of a causal role of ASK1 in PAH disease pathogenesis.
- 144Zhang, D.; Lin, J.; Han, J. Receptor-interacting protein (RIP) kinase family. Cell. Mol. Immunol. 2010, 7, 243– 249, DOI: 10.1038/cmi.2010.10[Crossref], [PubMed], [CAS], Google Scholar144https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXotlSms7w%253D&md5=e110b4cbd223b7ddef4855830c7d4156Receptor-interacting protein (RIP) kinase familyZhang, Duanwu; Lin, Juan; Han, JiahuaiCellular & Molecular Immunology (2010), 7 (4), 243-249CODEN: CMIEAO; ISSN:1672-7681. (NPG Nature Asia-Pacific)A review. Receptor-interacting protein (RIP) kinases are a group of threonine/serine protein kinases with a relatively conserved kinase domain but distinct non-kinase regions. A no. of different domain structures, such as death and caspase activation and recruitment domain (CARD) domains, were found in different RIP family members, and these domains should be keys in detg. the specific function of each RIP kinase. It is known that RIP kinases participate in different biol. processes, including those in innate immunity, but their downstream substrates are largely unknown. This review will give an overview of the structures and functions of RIP family members, and an update of recent progress in RIP kinase research.
- 145Declercq, W.; Vanden Berghe, T.; Vandenabeele, P. RIP kinases at the crossroads of cell death and survival. Cell 2009, 138, 229– 232, DOI: 10.1016/j.cell.2009.07.006[Crossref], [PubMed], [CAS], Google Scholar145https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtVSgtrzK&md5=5f75989020b487729d5c9112b246d9c5RIP kinases at the crossroads of cell death and survivalDeclercq, Wim; Vanden Berghe, Tom; Vandenabeele, PeterCell (Cambridge, MA, United States) (2009), 138 (2), 229-232CODEN: CELLB5; ISSN:0092-8674. (Cell Press)A review. Protein kinases of the receptor interacting protein (RIP) family collaborate with death receptor proteins to regulate cell death. Recent studies reveal that RIP3 kinase functions with RIP1 at the crossroads of apoptosis, necroptosis, and cell survival.
- 146Cuny, G. D.; Degterev, A. RIPK protein kinase family: Atypical lives of typical kinases. Semin. Cell Dev. Biol. 2020, DOI: 10.1016/j.semcdb.2020.06.014 .
- 147Martens, S.; Hofmans, S.; Declercq, W.; Augustyns, K.; Vandenabeele, P. Inhibitors targeting RIPK1/RIPK3: old and new drugs. Trends Pharmacol. Sci. 2020, 41, 209– 224, DOI: 10.1016/j.tips.2020.01.002[Crossref], [PubMed], [CAS], Google Scholar147https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhvFShsLc%253D&md5=fa5bbc5b08590333606d3de18f1dd61aInhibitors Targeting RIPK1/RIPK3: Old and New DrugsMartens, Sofie; Hofmans, Sam; Declercq, Wim; Augustyns, Koen; Vandenabeele, PeterTrends in Pharmacological Sciences (2020), 41 (3), 209-224CODEN: TPHSDY; ISSN:0165-6147. (Elsevier Ltd.)A review. The scaffolding function of receptor-interacting protein kinase 1 (RIPK1) regulates prosurvival signaling and inflammatory gene expression, while its kinase activity mediates both apoptosis and necroptosis; the latter involving RIPK3 kinase activity. The mutual transition between the scaffold and kinase functions of RIPK1 is regulated by (de)ubiquitylation and (de)phosphorylation. RIPK1-mediated cell death leads to disruption of epithelial barriers and/or release of damage-assocd. mol. patterns (DAMPs), cytokines, and chemokines, propagating inflammatory and degenerative diseases. Many drug development programs have pursued targeting RIPK1, and to a lesser extent RIPK3 kinase activity. In this review, we classify existing and novel small-mol. drugs based on their pharmacodynamic (PD) type I, II, and III binding mode. Finally, we discuss their applicability and therapeutic potential in inflammatory and degenerative exptl. disease models.
- 148Xu, J.; Wei, Q.; He, Z. Insight into the function of RIPK4 in keratinocyte differentiation and carcinogenesis. Front. Oncol. 2020, 10, 1562, DOI: 10.3389/fonc.2020.01562[Crossref], [PubMed], [CAS], Google Scholar148https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB38bot1aiug%253D%253D&md5=d253fdeea567ef4e2cb6b23c624cd31fInsight Into the Function of RIPK4 in Keratinocyte Differentiation and CarcinogenesisXu Jing; Wei Qichun; He ZhixingFrontiers in oncology (2020), 10 (), 1562 ISSN:2234-943X.The receptor-interacting protein kinase 4 (RIPK4), a member of the RIPK family, was originally described as an interaction partner of protein kinase C (PKC) β and PKCδ. RIPK4 is identified as a key regulator of keratinocyte differentiation, cutaneous inflammation, and cutaneous wound repair. The mechanism by which RIPK4 integrates upstream signals to initiate specific responses remains elusive. Previous studies have indicated that RIPK4 can regulate several signaling pathways, including the NF-κB, Wnt/β-catenin, and RAF/MEK/ERK pathways. Furthermore, RIPK4-related biological signaling pathways interact with each other to form a complex network. Mounting evidence suggests that RIPK4 is aberrantly expressed in various kinds of cancers. In several types of squamous cell carcinoma (SCC), the mutations that drive aggressive SCC have been found in RIPK4. In addition, the function of RIPK4 in carcinogenesis is probably tissue-specific, since RIPK4 can play a dual role as both a tumor promoter and a tumor suppressor in different tumor types. Therefore, RIPK4 may represent as an independent prognostic factor and a promising novel therapeutic target, which can be used to identify the risks of patients and guide personalized treatments. In future, RIPK4-interacting pathways and precise molecular targets need to be investigated in order to further elucidate the mechanisms underlying epidermal differentiation and carcinogenesis.
- 149Wegner, K. W.; Saleh, D.; Degterev, A. Complex pathologic roles of RIPK1 and RIPK3: moving beyond necroptosis. Trends Pharmacol. Sci. 2017, 38, 202– 225, DOI: 10.1016/j.tips.2016.12.005[Crossref], [PubMed], [CAS], Google Scholar149https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXlt12ltA%253D%253D&md5=296e25764f643a458906f2a9aac1df05Complex Pathologic Roles of RIPK1 and RIPK3: Moving Beyond NecroptosisWegner, Kelby W.; Saleh, Danish; Degterev, AlexeiTrends in Pharmacological Sciences (2017), 38 (3), 202-225CODEN: TPHSDY; ISSN:0165-6147. (Elsevier Ltd.)A review. A process of regulated necrosis, termed necroptosis, has been recognized as a major contributor to cell death and inflammation occurring under a wide range of pathol. settings. The core event in necroptosis is the formation of the detergent-insol. 'necrosome' complex of homologous Ser/Thr kinases, receptor protein interacting kinase 1 (RIPK1) and receptor interacting protein kinase 3 (RIPK3), which promotes phosphorylation of a key prodeath effector, mixed lineage kinase domain-like (MLKL), by RIPK3. Core necroptosis mediators are under multiple controls, which have been a subject of intense investigation. Addnl., non-necroptotic functions of these factors, primarily in controlling apoptosis and inflammatory responses, have also begun to emerge. This review will provide an overview of the current understanding of the human disease relevance of this pathway, and potential therapeutic strategies, targeting necroptosis mediators in various pathologies.
- 150Harris, P. A.; Berger, S. B.; Jeong, J. U.; Nagilla, R.; Bandyopadhyay, D.; Campobasso, N.; Capriotti, C. A.; Cox, J. A.; Dare, L.; Dong, X.; Eidam, P. M.; Finger, J. N.; Hoffman, S. J.; Kang, J.; Kasparcova, V.; King, B. W.; Lehr, R.; Lan, Y.; Leister, L. K.; Lich, J. D.; MacDonald, T. T.; Miller, N. A.; Ouellette, M. T.; Pao, C. S.; Rahman, A.; Reilly, M. A.; Rendina, A. R.; Rivera, E. J.; Schaeffer, M. C.; Sehon, C. A.; Singhaus, R. R.; Sun, H. H.; Swift, B. A.; Totoritis, R. D.; Vossenkamper, A.; Ward, P.; Wisnoski, D. D.; Zhang, D.; Marquis, R. W.; Gough, P. J.; Bertin, J. Discovery of a first-in-class Receptor interacting protein 1 (RIP1) kinase specific clinical candidate (GSK2982772) for the treatment of inflammatory diseases. J. Med. Chem. 2017, 60, 1247– 1261, DOI: 10.1021/acs.jmedchem.6b01751[ACS Full Text], [CAS], Google Scholar150https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXitVeksLk%253D&md5=ee0c3c60bb1351dff696490ac9edb1ccDiscovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory DiseasesHarris, Philip A.; Berger, Scott B.; Jeong, Jae U.; Nagilla, Rakesh; Bandyopadhyay, Deepak; Campobasso, Nino; Capriotti, Carol A.; Cox, Julie A.; Dare, Lauren; Dong, Xiaoyang; Eidam, Patrick M.; Finger, Joshua N.; Hoffman, Sandra J.; Kang, James; Kasparcova, Viera; King, Bryan W.; Lehr, Ruth; Lan, Yunfeng; Leister, Lara K.; Lich, John D.; MacDonald, Thomas T.; Miller, Nathan A.; Ouellette, Michael T.; Pao, Christina S.; Rahman, Attiq; Reilly, Michael A.; Rendina, Alan R.; Rivera, Elizabeth J.; Schaeffer, Michelle C.; Sehon, Clark A.; Singhaus, Robert R.; Sun, Helen H.; Swift, Barbara A.; Totoritis, Rachel D.; Vossenkamper, Anna; Ward, Paris; Wisnoski, David D.; Zhang, Daohua; Marquis, Robert W.; Gough, Peter J.; Bertin, JohnJournal of Medicinal Chemistry (2017), 60 (4), 1247-1261CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)RIP1 regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-mol. inhibitors of RIP1 kinase that are suitable for advancement into the clinic have yet to be described. Herein, the authors report the lead optimization of a benzoxazepinone hit from a DNA-encoded library and the discovery and profile of clin. candidate GSK2982772 (compd. I), currently in phase 2a clin. studies for psoriasis, rheumatoid arthritis, and ulcerative colitis. Compd. I potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking many TNF-dependent cellular responses. Highlighting its potential as a novel anti-inflammatory agent, the inhibitor was also able to reduce spontaneous prodn. of cytokines from human ulcerative colitis explants. The highly favorable physicochem. and ADMET properties of I, combined with high potency, led to a predicted low oral dose in humans.
- 151Yoshikawa, M.; Saitoh, M.; Katoh, T.; Seki, T.; Bigi, S. V.; Shimizu, Y.; Ishii, T.; Okai, T.; Kuno, M.; Hattori, H.; Watanabe, E.; Saikatendu, K. S.; Zou, H.; Nakakariya, M.; Tatamiya, T.; Nakada, Y.; Yogo, T. Discovery of 7-oxo-2,4,5,7-tetrahydro-6 H-pyrazolo[3,4- c]pyridine derivatives as potent, orally available, and brain-penetrating Receptor interacting protein 1 (RIP1) kinase inhibitors: analysis of structure-kinetic relationships. J. Med. Chem. 2018, 61, 2384– 2409, DOI: 10.1021/acs.jmedchem.7b01647[ACS Full Text], [CAS], Google Scholar151https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjtlOku78%253D&md5=a76ab7f12af03e277ba37d7ea08274c9Discovery of 7-Oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine Derivatives as Potent, Orally Available, and Brain-Penetrating Receptor Interacting Protein 1 (RIP1) Kinase Inhibitors: Analysis of Structure-Kinetic RelationshipsYoshikawa, Masato; Saitoh, Morihisa; Katoh, Taisuke; Seki, Tomohiro; Bigi, Simone V.; Shimizu, Yuji; Ishii, Tsuyoshi; Okai, Takuro; Kuno, Masako; Hattori, Harumi; Watanabe, Etsuro; Saikatendu, Kumar S.; Zou, Hua; Nakakariya, Masanori; Tatamiya, Takayuki; Nakada, Yoshihisa; Yogo, TakatoshiJournal of Medicinal Chemistry (2018), 61 (6), 2384-2409CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The authors report the discovery of 7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine derivs. as a novel class of receptor interacting protein 1 (RIP1) kinase inhibitors. On the basis of the overlay study between HTS hit 10 and GSK2982772 in RIP1 kinase, the authors designed and synthesized a novel class of RIP1 kinase inhibitor (11, (3S)-3-(2-Benzyl-4-oxo-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-5-methyl-2,3-dihydro-1,5-benzoxazepin-4(5H)-one trifluoroacetic acid) possessing moderate RIP1 kinase inhibitory activity and P-gp mediated efflux. The optimization of the core structure and the exploration of appropriate substituents utilizing SBDD approach led to the discovery of (22, (3S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-8-carbonitrile), a highly potent, orally available, and brain-penetrating RIP1 kinase inhibitor with excellent PK profiles. Compd. 22 significantly suppressed necroptotic cell death both in mouse and human cells. Oral administration of 22 (10 mg/kg, bid) attenuated disease progression in the mouse exptl. autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Moreover, anal. of structure-kinetic relationship (SKR) for the authors' novel chem. series was also discussed.
- 152Patel, S.; Webster, J. D.; Varfolomeev, E.; Kwon, Y. C.; Cheng, J. H.; Zhang, J.; Dugger, D. L.; Wickliffe, K. E.; Maltzman, A.; Sujatha-Bhaskar, S.; Bir Kohli, P.; Ramaswamy, S.; Deshmukh, G.; Liederer, B. M.; Fong, R.; Hamilton, G.; Lupardus, P.; Caplazi, P.; Lee, W. P.; van Lookeren Campagne, M.; Johnson, A.; McKenzie, B. S.; Junttila, M. R.; Newton, K.; Vucic, D. RIP1 inhibition blocks inflammatory diseases but not tumor growth or metastases. Cell Death Differ. 2020, 27, 161– 175, DOI: 10.1038/s41418-019-0347-0[Crossref], [PubMed], [CAS], Google Scholar152https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFSmsbjO&md5=d3639164630df8f3dc21403367aef1c6RIP1 inhibition blocks inflammatory diseases but not tumor growth or metastasisPatel, Snahel; Webster, Joshua D.; Varfolomeev, Eugene; Kwon, Youngsu C.; Cheng, Jason H.; Zhang, Juan; Dugger, Debra L.; Wickliffe, Kate E.; Maltzman, Allie; Sujatha-Bhaskar, Swathi; Bir Kohli, Pawan; Ramaswamy, Sreema; Deshmukh, Gauri; Liederer, Bianca M.; Fong, Rina; Hamilton, Greg; Lupardus, Patrick; Caplazi, Patrick; Lee, Wyne P.; van Lookeren Campagne, Menno; Johnson, Adam; McKenzie, Brent S.; Junttila, Melissa R.; Newton, Kim; Vucic, DomagojCell Death & Differentiation (2020), 27 (1), 161-175CODEN: CDDIEK; ISSN:1350-9047. (Nature Research)The kinase RIP1 acts in multiple signaling pathways to regulate inflammatory responses and it can trigger both apoptosis and necroptosis. Its kinase activity has been implicated in a range of inflammatory, neurodegenerative, and oncogenic diseases. Here, we explore the effect of inhibiting RIP1 genetically, using knock-in mice that express catalytically inactive RIP1 D138N, or pharmacol., using the murine-potent inhibitor GNE684. Inhibition of RIP1 reduced collagen antibody-induced arthritis, and prevented skin inflammation caused by mutation of Sharpin, or colitis caused by deletion of Nemo from intestinal epithelial cells. Conversely, inhibition of RIP1 had no effect on tumor growth or survival in pancreatic tumor models driven by mutant Kras, nor did it reduce lung metastases in a B16 melanoma model. Collectively, our data emphasize a role for the kinase activity of RIP1 in certain inflammatory disease models, but question its relevance to tumor progression and metastasis.
- 153Harris, P. A.; Faucher, N.; George, N.; Eidam, P. M.; King, B. W.; White, G. V.; Anderson, N. A.; Bandyopadhyay, D.; Beal, A. M.; Beneton, V.; Berger, S. B.; Campobasso, N.; Campos, S.; Capriotti, C. A.; Cox, J. A.; Daugan, A.; Donche, F.; Fouchet, M. H.; Finger, J. N.; Geddes, B.; Gough, P. J.; Grondin, P.; Hoffman, B. L.; Hoffman, S. J.; Hutchinson, S. E.; Jeong, J. U.; Jigorel, E.; Lamoureux, P.; Leister, L. K.; Lich, J. D.; Mahajan, M. K.; Meslamani, J.; Mosley, J. E.; Nagilla, R.; Nassau, P. M.; Ng, S. L.; Ouellette, M. T.; Pasikanti, K. K.; Potvain, F.; Reilly, M. A.; Rivera, E. J.; Sautet, S.; Schaeffer, M. C.; Sehon, C. A.; Sun, H.; Thorpe, J. H.; Totoritis, R. D.; Ward, P.; Wellaway, N.; Wisnoski, D. D.; Woolven, J. M.; Bertin, J.; Marquis, R. W. Discovery and lead-optimization of 4,5-dihydropyrazoles as mono-kinase selective, orally bioavailable and efficacious inhibitors of Receptor interacting protein 1 (RIP1) kinase. J. Med. Chem. 2019, 62, 5096– 5110, DOI: 10.1021/acs.jmedchem.9b00318[ACS Full Text], [CAS], Google Scholar153https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXot1Sgsb8%253D&md5=eb3cdf239442f7364f51a79a56d43cbdDiscovery and Lead-Optimization of 4,5-Dihydropyrazoles as Mono-Kinase Selective, Orally Bioavailable and Efficacious Inhibitors of Receptor Interacting Protein 1 (RIP1) KinaseHarris, Philip A.; Faucher, Nicolas; George, Nicolas; Eidam, Patrick M.; King, Bryan W.; White, Gemma V.; Anderson, Niall A.; Bandyopadhyay, Deepak; Beal, Allison M.; Beneton, Veronique; Berger, Scott B.; Campobasso, Nino; Campos, Sebastien; Capriotti, Carol A.; Cox, Julie A.; Daugan, Alain; Donche, Frederic; Fouchet, Marie-Helene; Finger, Joshua N.; Geddes, Brad; Gough, Peter J.; Grondin, Pascal; Hoffman, Bonnie L.; Hoffman, Sandra J.; Hutchinson, Susan E.; Jeong, Jae U.; Jigorel, Emilie; Lamoureux, Pauline; Leister, Lara K.; Lich, John D.; Mahajan, Mukesh K.; Meslamani, Jamel; Mosley, Julie E.; Nagilla, Rakesh; Nassau, Pamela M.; Ng, Sze-Ling; Ouellette, Michael T.; Pasikanti, Kishore K.; Potvain, Florent; Reilly, Michael A.; Rivera, Elizabeth J.; Sautet, Stephane; Schaeffer, Michelle C.; Sehon, Clark A.; Sun, Helen; Thorpe, James H.; Totoritis, Rachel D.; Ward, Paris; Wellaway, Natalie; Wisnoski, David D.; Woolven, James M.; Bertin, John; Marquis, Robert W.Journal of Medicinal Chemistry (2019), 62 (10), 5096-5110CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)RIP1 kinase regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including inflammatory and neurol. diseases. Currently, RIP1 kinase inhibitors have advanced into early clin. trials for evaluation in inflammatory diseases such as psoriasis, rheumatoid arthritis, and ulcerative colitis and neurol. diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. In this paper, we report on the design of potent and highly selective dihydropyrazole (DHP) RIP1 kinase inhibitors starting from a high-throughput screen and the lead-optimization of this series from a lead with minimal rat oral exposure to the identification of dihydropyrazole 77 with good pharmacokinetic profiles in multiple species. Addnl., we identified a potent murine RIP1 kinase inhibitor 76 as a valuable in vivo tool mol. suitable for evaluating the role of RIP1 kinase in chronic models of disease. DHP 76 showed efficacy in mouse models of both multiple sclerosis and human retinitis pigmentosa.
- 154Harris, P. A.; Marinis, J. M.; Lich, J. D.; Berger, S. B.; Chirala, A.; Cox, J. A.; Eidam, P. M.; Finger, J. N.; Gough, P. J.; Jeong, J. U.; Kang, J.; Kasparcova, V.; Leister, L. K.; Mahajan, M. K.; Miller, G.; Nagilla, R.; Ouellette, M. T.; Reilly, M. A.; Rendina, A. R.; Rivera, E. J.; Sun, H. H.; Thorpe, J. H.; Totoritis, R. D.; Wang, W.; Wu, D.; Zhang, D.; Bertin, J.; Marquis, R. W. Identification of a RIP1 kinase inhibitor clinical candidate (GSK3145095) for the treatment of pancreatic cancer. ACS Med. Chem. Lett. 2019, 10, 857– 862, DOI: 10.1021/acsmedchemlett.9b00108[ACS Full Text], [CAS], Google Scholar154https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXptFymu7g%253D&md5=3e4783b47ed7240e15ae537749f20f2fIdentification of a RIP1 Kinase Inhibitor Clinical Candidate (GSK3145095) for the Treatment of Pancreatic CancerHarris, Philip A.; Marinis, Jill M.; Lich, John D.; Berger, Scott B.; Chirala, Anirudh; Cox, Julie A.; Eidam, Patrick M.; Finger, Joshua N.; Gough, Peter J.; Jeong, Jae U.; Kang, James; Kasparcova, Viera; Leister, Lara K.; Mahajan, Mukesh K.; Miller, George; Nagilla, Rakesh; Ouellette, Michael T.; Reilly, Michael A.; Rendina, Alan R.; Rivera, Elizabeth J.; Sun, Helen H.; Thorpe, James H.; Totoritis, Rachel D.; Wang, Wei; Wu, Dongling; Zhang, Daohua; Bertin, John; Marquis, Robert W.ACS Medicinal Chemistry Letters (2019), 10 (6), 857-862CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)RIP1 regulates cell death and inflammation and is believed to play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases and cancer. While small-mol. inhibitors of RIP1 kinase have been advanced to the clinic for inflammatory diseases and CNS indications, RIP1 inhibitors for oncol. indications have yet to be described. Herein we report on the discovery and profile of GSK3145095 (compd. 6). Compd. 6 potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking RIP1 kinase-dependent cellular responses. Highlighting its potential as a novel cancer therapy, the inhibitor was also able to promote a tumor suppressive T cell phenotype in pancreatic adenocarcinoma organ cultures. Compd. 6 is currently in phase 1 clin. studies for pancreatic adenocarcinoma and other selected solid tumors.
- 155Mukherjee, T.; Hovingh, E. S.; Foerster, E. G.; Abdel-Nour, M.; Philpott, D. J.; Girardin, S. E. NOD1 and NOD2 in inflammation, immunity and disease. Arch. Biochem. Biophys. 2019, 670, 69– 81, DOI: 10.1016/j.abb.2018.12.022[Crossref], [PubMed], [CAS], Google Scholar155https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitFGlsL4%253D&md5=7ef01b0d9c2b3bd6b28e60508af3b9dcNOD1 and NOD2 in inflammation, immunity and diseaseMukherjee, Tapas; Hovingh, Elise Sofie; Foerster, Elisabeth G.; Abdel-Nour, Mena; Philpott, Dana J.; Girardin, Stephen E.Archives of Biochemistry and Biophysics (2019), 670 (), 69-81CODEN: ABBIA4; ISSN:0003-9861. (Elsevier B.V.)A review. NOD1 and NOD2 are related intracellular sensors of bacterial peptidoglycan and belong to the Nod-like receptor (NLR) family of innate immune proteins that play fundamental and pleiotropic roles in host defense against infection and in the control of inflammation. The importance of these proteins is also highlighted by the genetic assocn. between single nucleotide polymorphisms in NOD2 and susceptibility to Crohn's disease, an inflammatory bowel disease. At the cellular level, recent efforts have delineated the signaling pathways triggered following activation of NOD1 and NOD2, and the interplay with various cellular processes, such as autophagy. In vivo studies have revealed the importance of NOD-dependent host defense in models of infection, and a crucial area of investigation focuses on understanding the role of NOD1 and NOD2 at the intestinal mucosa, as this is of prime importance for understanding the etiol. of Crohn's disease.
- 156Caruso, R.; Warner, N.; Inohara, N.; Nunez, G. NOD1 and NOD2: signaling, host defense, and inflammatory disease. Immunity 2014, 41, 898– 908, DOI: 10.1016/j.immuni.2014.12.010[Crossref], [PubMed], [CAS], Google Scholar156https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXislyqsg%253D%253D&md5=da20e3b76c185e91da9168b011bc0b78NOD1 and NOD2: Signaling, Host Defense, and Inflammatory DiseaseCaruso, Roberta; Warner, Neil; Inohara, Naohiro; Nunez, GabrielImmunity (2014), 41 (6), 898-908CODEN: IUNIEH; ISSN:1074-7613. (Elsevier Inc.)A review. The nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2, the founding members of the intracellular NOD-like receptor family, sense conserved motifs in bacterial peptidoglycan and induce proinflammatory and antimicrobial responses. Here, we discuss recent developments about the mechanisms by which NOD1 and NOD2 are activated by bacterial ligands, the regulation of their signaling pathways, and their role in host defense and inflammatory disease. Several routes for the entry of peptidoglycan ligands to the host cytosol to trigger activation of NOD1 and NOD2 have been elucidated. Furthermore, genetic screens and biochem. analyses have revealed mechanisms that regulate NOD1 and NOD2 signaling. Finally, recent studies have suggested several mechanisms to account for the link between NOD2 variants and susceptibility to Crohn's disease. Further understanding of NOD1 and NOD2 should provide new insight into the pathogenesis of disease and the development of new strategies to treat inflammatory and infectious disorders.
- 157Tigno-Aranjuez, J. T.; Benderitter, P.; Rombouts, F.; Deroose, F.; Bai, X.; Mattioli, B.; Cominelli, F.; Pizarro, T. T.; Hoflack, J.; Abbott, D. W. In vivo inhibition of RIPK2 kinase alleviates inflammatory disease. J. Biol. Chem. 2014, 289, 29651– 29664, DOI: 10.1074/jbc.M114.591388[Crossref], [PubMed], [CAS], Google Scholar157https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVSmt77K&md5=db1b6a092a8f61888702db41576892a9In Vivo Inhibition of RIPK2 Kinase Alleviates Inflammatory DiseaseTigno-Aranjuez, Justine T.; Benderitter, Pascal; Rombouts, Frederik; Deroose, Frederik; Bai, XiaoDong; Mattioli, Benedetta; Cominelli, Fabio; Pizarro, Theresa T.; Hoflack, Jan; Abbott, Derek W.Journal of Biological Chemistry (2014), 289 (43), 29651-29664CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)The RIPK2 kinase transduces signaling downstream of the intracellular peptidoglycan sensors NOD1 and NOD2 to promote a productive inflammatory response. However, excessive NOD2 signaling has been assocd. with numerous diseases, including inflammatory bowel disease (IBD), sarcoidosis and inflammatory arthritis, making pharmacol. inhibition of RIPK2 an appealing strategy. In this work, the authors report the generation, identification, and evaluation of novel RIPK2 specific inhibitors. These compds. potently inhibit the RIPK2 tyrosine kinase activity in in vitro biochem. assays and cellular assays, as well as effectively reduce RIPK2-mediated effects in an in vivo peritonitis model. In conjunction with the development of these inhibitors, the authors have also defined a panel of genes whose expression is regulated by RIPK2 kinase activity. Such RIPK2 activation markers may serve as a useful tool for predicting settings likely to benefit from RIPK2 inhibition. Using these markers and the FDA-approved RIPK2 inhibitor Gefitinib, the authors show that pharmacol. RIPK2 inhibition drastically improves disease in a spontaneous model of Crohn Disease-like ileitis. Furthermore, using novel RIPK2-specific inhibitors, the authors show that cellular recruitment is inhibited in an in vivo peritonitis model. Altogether, the data presented in this work provides a strong rationale for further development and optimization of RIPK2-targeted pharmaceuticals and diagnostics.
- 158Haile, P. A.; Votta, B. J.; Marquis, R. W.; Bury, M. J.; Mehlmann, J. F.; Singhaus, R., Jr.; Charnley, A. K.; Lakdawala, A. S.; Convery, M. A.; Lipshutz, D. B.; Desai, B. M.; Swift, B.; Capriotti, C. A.; Berger, S. B.; Mahajan, M. K.; Reilly, M. A.; Rivera, E. J.; Sun, H. H.; Nagilla, R.; Beal, A. M.; Finger, J. N.; Cook, M. N.; King, B. W.; Ouellette, M. T.; Totoritis, R. D.; Pierdomenico, M.; Negroni, A.; Stronati, L.; Cucchiara, S.; Ziolkowski, B.; Vossenkamper, A.; MacDonald, T. T.; Gough, P. J.; Bertin, J.; Casillas, L. N. The identification and pharmacological characterization of 6-(tert-butylsulfonyl)-N-(5-fluoro-1h-indazol-3-yl)quinolin-4-amine (GSK583), a highly potent and selective inhibitor of RIP2 kinase. J. Med. Chem. 2016, 59, 4867– 4880, DOI: 10.1021/acs.jmedchem.6b00211[ACS Full Text], [CAS], Google Scholar158https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xms1GqsLs%253D&md5=74a178c9f055232de8a729bd254fce3eThe Identification and Pharmacological Characterization of 6-(tert-Butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine (GSK583), a Highly Potent and Selective Inhibitor of RIP2 KinaseHaile, Pamela A.; Votta, Bartholomew J.; Marquis, Robert W.; Bury, Michael J.; Mehlmann, John F.; Singhaus, Robert; Charnley, Adam K.; Lakdawala, Ami S.; Convery, Maire A.; Lipshutz, David B.; Desai, Biva M.; Swift, Barbara; Capriotti, Carol A.; Berger, Scott B.; Majahan, Mukesh K.; Reilly, Michael A.; Rivera, Elizabeth J.; Sun, Helen H.; Nagilla, Rakesh; Beal, Allison M.; Finger, Joshua N.; Cook, Michael N.; King, Bryan W.; Ouellette, Michael T.; Totoritis, Rachel D.; Pierdomenico, Maria; Negroni, Anna; Stronati, Laura; Cucchiara, Salvatore; Ziolkowski, Bartlomiej; Vossenkamper, Anna; MacDonald, Thomas T.; Gough, Peter J.; Bertin, John; Casillas, Linda N.Journal of Medicinal Chemistry (2016), 59 (10), 4867-4880CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)RIP2 kinase is a central component of the innate immune system and enables downstream signaling following activation of the pattern recognition receptors NOD1 and NOD2, leading to the prodn. of inflammatory cytokines. Recently, several inhibitors of RIP2 kinase have been disclosed that have contributed to the fundamental understanding of the role of RIP2 in this pathway. However, because they lack either broad kinase selectivity or strong affinity for RIP2, these tools have only limited utility to assess the role of RIP2 in complex environments. We present, herein, the discovery and pharmacol. characterization of GSK583 (I), a next-generation RIP2 inhibitor possessing exquisite selectivity and potency. Having demonstrated the pharmacol. precision of this tool compd., we report its use in elucidating the role of RIP2 kinase in a variety of in vitro, in vivo, and ex vivo expts., further clarifying our understanding of the role of RIP2 in NOD1 and NOD2 mediated disease pathogenesis.
- 159Haile, P. A.; Casillas, L. N.; Bury, M. J.; Mehlmann, J. F.; Singhaus, R., Jr.; Charnley, A. K.; Hughes, T. V.; DeMartino, M. P.; Wang, G. Z.; Romano, J. J.; Dong, X.; Plotnikov, N. V.; Lakdawala, A. S.; Convery, M. A.; Votta, B. J.; Lipshutz, D. B.; Desai, B. M.; Swift, B.; Capriotti, C. A.; Berger, S. B.; Mahajan, M. K.; Reilly, M. A.; Rivera, E. J.; Sun, H. H.; Nagilla, R.; LePage, C.; Ouellette, M. T.; Totoritis, R. D.; Donovan, B. T.; Brown, B. S.; Chaudhary, K. W.; Gough, P. J.; Bertin, J.; Marquis, R. W. Identification of quinoline-based RIP2 kinase inhibitors with an improved therapeutic index to the herg ion channel. ACS Med. Chem. Lett. 2018, 9, 1039– 1044, DOI: 10.1021/acsmedchemlett.8b00344[ACS Full Text], [CAS], Google Scholar159https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslyjsrnJ&md5=64f2cfeb587cf336339fe800ce5cb96bIdentification of Quinoline-Based RIP2 Kinase Inhibitors with an Improved Therapeutic Index to the hERG Ion ChannelHaile, Pamela A.; Casillas, Linda N.; Bury, Michael J.; Mehlmann, John F.; Singhaus, Robert; Charnley, Adam K.; Hughes, Terry V.; DeMartino, Michael P.; Wang, Gren Z.; Romano, Joseph J.; Dong, Xiaoyang; Plotnikov, Nikolay V.; Lakdawala, Ami S.; Convery, Maire A.; Votta, Bartholomew J.; Lipshutz, David B.; Desai, Biva M.; Swift, Barbara; Capriotti, Carol A.; Berger, Scott B.; Mahajan, Mukesh K.; Reilly, Michael A.; Rivera, Elizabeth J.; Sun, Helen H.; Nagilla, Rakesh; LePage, Carol; Ouellette, Michael T.; Totoritis, Rachel D.; Donovan, Brian T.; Brown, Barry S.; Chaudhary, Khuram W.; Gough, Peter J.; Bertin, John; Marquis, Robert W.ACS Medicinal Chemistry Letters (2018), 9 (10), 1039-1044CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)RIP2 kinase was recently identified as a therapeutic target for a variety of autoimmune diseases. We have reported previously a selective 4-aminoquinoline-based RIP2 inhibitor GSK583 and demonstrated its effectiveness in blocking downstream NOD2 signaling in cellular models, rodent in vivo models, and human ex vivo disease models. While this tool compd. was valuable in validating the biol. pathway, it suffered from activity at the hERG ion channel and a poor PK/PD profile thereby limiting progression of this analog. Herein, we detail our efforts to improve both this off-target liability as well as the PK/PD profile of this series of inhibitors through modulation of lipophilicity and strengthening hinge binding ability. These efforts have led to inhibitor I, which possesses high binding affinity for the ATP pocket of RIP2 (IC50 = 1 nM) and inhibition of downstream cytokine prodn. in human whole blood (IC50 = 10 nM) with reduced hERG activity (14 μM).
- 160Haile, P. A.; Casillas, L. N.; Votta, B. J.; Wang, G. Z.; Charnley, A. K.; Dong, X.; Bury, M. J.; Romano, J. J.; Mehlmann, J. F.; King, B. W.; Erhard, K. F.; Hanning, C. R.; Lipshutz, D. B.; Desai, B. M.; Capriotti, C. A.; Schaeffer, M. C.; Berger, S. B.; Mahajan, M. K.; Reilly, M. A.; Nagilla, R.; Rivera, E. J.; Sun, H. H.; Kenna, J. K.; Beal, A. M.; Ouellette, M. T.; Kelly, M.; Stemp, G.; Convery, M. A.; Vossenkamper, A.; MacDonald, T. T.; Gough, P. J.; Bertin, J.; Marquis, R. W. Discovery of a first-in-class Receptor interacting protein 2 (RIP2) kinase specific clinical candidate, 2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl dihydrogen phosphate, for the treatment of inflammatory diseases. J. Med. Chem. 2019, 62, 6482– 6494, DOI: 10.1021/acs.jmedchem.9b00575[ACS Full Text], [CAS], Google Scholar160https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtlams77M&md5=c25c648d6ff1d2f1c149e4c37c712026Discovery of a First-in-Class Receptor Interacting Protein 2 (RIP2) Kinase Specific Clinical Candidate, 2-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl Dihydrogen Phosphate, for the Treatment of Inflammatory DiseasesHaile, Pamela A.; Casillas, Linda N.; Votta, Bartholomew J.; Wang, Gren Z.; Charnley, Adam K.; Dong, Xiaoyang; Bury, Michael J.; Romano, Joseph J.; Mehlmann, John F.; King, Bryan W.; Erhard, Karl F.; Hanning, Charles R.; Lipshutz, David B.; Desai, Biva M.; Capriotti, Carol A.; Schaeffer, Michelle C.; Berger, Scott B.; Mahajan, Mukesh K.; Reilly, Michael A.; Nagilla, Rakesh; Rivera, Elizabeth J.; Sun, Helen H.; Kenna, John K.; Beal, Allison M.; Ouellette, Michael T.; Kelly, Mike; Stemp, Gillian; Convery, Maire A.; Vossenkamper, Anna; MacDonald, Thomas T.; Gough, Peter J.; Bertin, John; Marquis, Robert W.Journal of Medicinal Chemistry (2019), 62 (14), 6482-6494CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)RIP2 kinase has been identified as a key signal transduction partner in the NOD2 pathway contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-mol. inhibitors of RIP2 kinase or its signaling partners on the NOD2 pathway that are suitable for advancement into the clinic have yet to be described. Herein, we report our discovery and profile of the prodrug clin. compd., inhibitor 3, currently in phase 1 clin. studies. Compd. 3 potently binds to RIP2 kinase with good kinase specificity and has excellent activity in blocking many proinflammatory cytokine responses in vivo and in human IBD explant samples. The highly favorable physicochem. and ADMET properties of 3 combined with high potency led to a predicted low oral dose in humans.
- 161Haffner, C. D.; Charnley, A. K.; Aquino, C. J.; Casillas, L.; Convery, M. A.; Cox, J. A.; Elban, M. A.; Goodwin, N. C.; Gough, P. J.; Haile, P. A.; Hughes, T. V.; Knapp-Reed, B.; Kreatsoulas, C.; Lakdawala, A. S.; Li, H.; Lian, Y.; Lipshutz, D.; Mehlmann, J. F.; Ouellette, M.; Romano, J.; Shewchuk, L.; Shu, A.; Votta, B. J.; Zhou, H.; Bertin, J.; Marquis, R. W. Discovery of pyrazolocarboxamides as potent and selective Receptor interacting protein 2 (RIP2) kinase inhibitors. ACS Med. Chem. Lett. 2019, 10, 1518– 1523, DOI: 10.1021/acsmedchemlett.9b00141[ACS Full Text], [CAS], Google Scholar161https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFChs77P&md5=8e77a9908acc704196eee7d336f67c62Discovery of Pyrazolocarboxamides as Potent and Selective Receptor Interacting Protein 2 (RIP2) Kinase InhibitorsHaffner, Curt D.; Charnley, Adam K.; Aquino, Christopher J.; Casillas, Linda; Convery, Maire A.; Cox, Julie A.; Elban, Mark A.; Goodwin, Nicole C.; Gough, Peter J.; Haile, Pamela A.; Hughes, Terry V.; Knapp-Reed, Beth; Kreatsoulas, Constantine; Lakdawala, Ami S.; Li, Huijie; Lian, Yiqian; Lipshutz, David; Mehlmann, John F.; Ouellette, Michael; Romano, Joseph; Shewchuk, Lisa; Shu, Arthur; Votta, Bartholomew J.; Zhou, Huiqiang; Bertin, John; Marquis, Robert W.ACS Medicinal Chemistry Letters (2019), 10 (11), 1518-1523CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Herein we report the discovery of pyrazolocarboxamides as novel, potent, and kinase selective inhibitors of receptor interacting protein 2 kinase (RIP2). Fragment based screening and design principles led to the identification of the inhibitor series, and X-ray crystallog. was used to inform key structural changes. Through key substitutions about the N1 and C5 N positions on the pyrazole ring significant kinase selectivity and potency were achieved. Bridged bicyclic pyrazolocarboxamide 11 represents a selective and potent inhibitor of RIP2 and will allow for a more detailed investigation of RIP2 inhibition as a therapeutic target for autoinflammatory disorders.
- 162He, X.; Da Ros, S.; Nelson, J.; Zhu, X.; Jiang, T.; Okram, B.; Jiang, S.; Michellys, P. Y.; Iskandar, M.; Espinola, S.; Jia, Y.; Bursulaya, B.; Kreusch, A.; Gao, M. Y.; Spraggon, G.; Baaten, J.; Clemmer, L.; Meeusen, S.; Huang, D.; Hill, R.; Nguyen-Tran, V.; Fathman, J.; Liu, B.; Tuntland, T.; Gordon, P.; Hollenbeck, T.; Ng, K.; Shi, J.; Bordone, L.; Liu, H. Identification of potent and selective RIPK2 inhibitors for the treatment of inflammatory diseases. ACS Med. Chem. Lett. 2017, 8, 1048– 1053, DOI: 10.1021/acsmedchemlett.7b00258[ACS Full Text], [CAS], Google Scholar162https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFOjtLjJ&md5=87e32df13c63a9cd16b20652ae96b36aIdentification of Potent and Selective RIPK2 Inhibitors for the Treatment of Inflammatory DiseasesHe, Xiaohui; Da Ros, Sara; Nelson, John; Zhu, Xuefeng; Jiang, Tao; Okram, Barun; Jiang, Songchun; Michellys, Pierre-Yves; Iskandar, Maya; Espinola, Sheryll; Jia, Yong; Bursulaya, Badry; Kreusch, Andreas; Gao, Mu-Yun; Spraggon, Glen; Baaten, Janine; Clemmer, Leah; Meeusen, Shelly; Huang, David; Hill, Robert; Nguyen-Tran, Van; Fathman, John; Liu, Bo; Tuntland, Tove; Gordon, Perry; Hollenbeck, Thomas; Ng, Kenneth; Shi, Jian; Bordone, Laura; Liu, HongACS Medicinal Chemistry Letters (2017), 8 (10), 1048-1053CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)NOD2 (nucleotide-binding oligomerization domain-contg. protein 2) is an internal pattern recognition receptor that recognizes bacterial peptidoglycan and stimulates host immune responses. Dysfunction of NOD2 pathway has been assocd. with a no. of autoinflammatory disorders. To date, direct inhibitors of NOD2 have not been described due to tech. challenges of targeting the oligomeric protein complex. Receptor interacting protein kinase 2 (RIPK2) is an intracellular serine/threonine/tyrosine kinase, a key signaling partner, and an obligate kinase for NOD2. As such, RIPK2 represents an attractive target to probe the pathol. roles of NOD2 pathway. To search for selective RIPK2 inhibitors, the authors employed virtual library screening (VLS) and structure based design that eventually led to a potent and selective RIPK2 inhibitor 8 (4-(7-ethoxy-6-(isopropylsulfonyl)imidazo[1,2-a]pyridin-3-yl)-6-fluoropyridin-2-amine) with excellent oral bioavailability, which was used to evaluate the effects of inhibition of RIPK2 in various in vitro assays and ex vivo and in vivo pharmacodynamic models.
- 163Suzuki, N.; Suzuki, S.; Duncan, G. S.; Millar, D. G.; Wada, T.; Mirtsos, C.; Takada, H.; Wakeham, A.; Itie, A.; Li, S.; Penninger, J. M.; Wesche, H.; Ohashi, P. S.; Mak, T. W.; Yeh, W. C. Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Nature 2002, 416, 750– 756, DOI: 10.1038/nature736[Crossref], [PubMed], [CAS], Google Scholar163https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XjtVKksb4%253D&md5=3cab6526ac8aa58532f50c5bfb364e5cSevere impairment of interleukin-1 and Toll-like receptor signaling in mice lacking IRAK-4Suzuki, N.; Suzuki, S.; Duncan, G. S.; Millar, D. G.; Wada, T.; Mirtsos, C.; Takada, H.; Wakeham, A.; Itie, A.; Li, S.; Penninger, J. M.; Wesche, H.; Ohashi, P. S.; Mak, T. W.; Yeh, W. C.Nature (London, United Kingdom) (2002), 416 (6882), 750-756CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Toll-like receptors (TLRs), which recognize pathogen-assocd. mol. patterns, and members of the pro-inflammatory interleukin-1 receptor (IL-1R) family, share homologies in their cytoplasmic domains called Toll/IL-1R/plant R gene homol. (TIR) domains. Intracellular signaling mechanisms mediated by TLRs are similar, with MyD88 and TRAF6 having crit. roles. Signal transduction between MyD88 and TRAF6 is known to involve the serine-threonine kinase IL-1 receptor-assocd. kinase 1 (IRAK-1) and two homologous proteins, IRAK-2 and IRAK-M. However, the physiol. functions of the IRAK mols. remain unclear, and gene-targeting studies have shown that IRAK-1 is only partially required for IL-1R and TLR signaling. Here we show by gene-targeting that IRAK-4, an IRAK mol. closely related to the Drosophila Pelle protein, is indispensable for the responses of animals and cultured cells to IL-1 and ligands that stimulate various TLRs. IRAK-4-deficient animals are completely resistant to a LD of lipopolysaccharide (LPS). In addn., animals lacking IRAK-4 are severely impaired in their responses to viral and bacterial challenges. Our results indicate that IRAK-4 has an essential role in innate immunity.
- 164Ku, C. L.; von Bernuth, H.; Picard, C.; Zhang, S. Y.; Chang, H. H.; Yang, K.; Chrabieh, M.; Issekutz, A. C.; Cunningham, C. K.; Gallin, J.; Holland, S. M.; Roifman, C.; Ehl, S.; Smart, J.; Tang, M.; Barrat, F. J.; Levy, O.; McDonald, D.; Day-Good, N. K.; Miller, R.; Takada, H.; Hara, T.; Al-Hajjar, S.; Al-Ghonaium, A.; Speert, D.; Sanlaville, D.; Li, X.; Geissmann, F.; Vivier, E.; Marodi, L.; Garty, B. Z.; Chapel, H.; Rodriguez-Gallego, C.; Bossuyt, X.; Abel, L.; Puel, A.; Casanova, J. L. Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity. J. Exp. Med. 2007, 204, 2407– 2422, DOI: 10.1084/jem.20070628[Crossref], [PubMed], [CAS], Google Scholar164https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFCntrbP&md5=995f31b8684f666d83b752908323ce1eSelective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunityKu, Cheng-Lung; von Bernuth, Horst; Picard, Capucine; Zhang, Shen-Ying; Chang, Huey-Hsuan; Yang, Kun; Chrabieh, Maya; Issekutz, Andrew C.; Cunningham, Coleen K.; Gallin, John; Holland, Steven M.; Roifman, Chaim; Ehl, Stephan; Smart, Joanne; Tang, Mimi; Barrat, Franck J.; Levy, Ofer; McDonald, Douglas; Day-Good, Noorbibi K.; Miller, Richard; Takada, Hidetoshi; Hara, Toshiro; Al-Hajjar, Sami; Al-Ghonaium, Abdulaziz; Speert, David; Sanlaville, Damien; Li, Xiaoxia; Geissmann, Frederic; Vivier, Eric; Marodi, Laszlo; Garty, Ben-Zion; Chapel, Helen; Rodriguez-Gallego, Carlos; Bossuyt, Xavier; Abel, Laurent; Puel, Anne; Casanova, Jean-LaurentJournal of Experimental Medicine (2007), 204 (10), 2407-2422CODEN: JEMEAV; ISSN:0022-1007. (Rockefeller University Press)Human interleukin (IL) 1 receptor-assocd. kinase 4 (IRAK-4) deficiency is a recently discovered primary immunono-deficiency that impairs Toll/IL-1R immunity, except for the Toll-like receptor (TLR) 3- an TLR4-interferon (IRN)-α/β pathways. The clin. and immunol. phenotype remains largely unknown. We diagnose up to 28 patients with IRAK-4 deficiency, tested blood TLR responses for individual leukocyte subsets, and TLR responses for multiple cytokines. The patients' peripheral blood mononuclear cells (PBMCs) did not induce the 11 non-IFN cytokines tested upon activation with TLR agonists other than the nonspecific TLR3 agonist poly(I:C). The patients' individual cell subsets from both myeloid (granulocytes, monocytes, monocyte-derived dendritic cells [MDDCs], myeloid DCs [MDCs], and plasmacytoid DCs) and lymphoid (B, T, and NK cells) lineages did not respond to the TLR agonists that stimulated control cells, with the exception of residual responses to poly(I:C) and lipopolysaccharide in MDCs and MDDCs. Most patients (22 out of 28; 79%) suffered from invasive pneumococcal disease, which was often recurrent (13 out of 22; 59%). Other infections were rare, with the exception of severe staphylococcal disease (9 out of 28; 32%). Almost half of the patients died (12 out of 28; 43%). No death and no invasive infection occurred in patients older than 8 and 14 yr. resp. The IRAK-4-dependent TLRs and IL-1Rs are therefore vital for childhood immunity to pyogenic bacteria, particularly Streptococcus pneumoniae. Conversely, IRAK-4-dependent human TLRs appear to play a redundant role in protective immunity to most infections, at most limited to childhood immunity to some pyogenic bacteria.
- 165Chaudhary, D.; Robinson, S.; Romero, D. L. Recent advances in the discovery of small molecule inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4) as a therapeutic target for inflammation and oncology disorders. J. Med. Chem. 2015, 58, 96– 110, DOI: 10.1021/jm5016044[ACS Full Text], [CAS], Google Scholar165https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVCjsLzL&md5=795797f7f3f07597ecd0b5899498804bRecent Advances in the Discovery of Small Molecule Inhibitors of Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) as a Therapeutic Target for Inflammation and Oncology DisordersChaudhary, Divya; Robinson, Shaughnessy; Romero, Donna L.Journal of Medicinal Chemistry (2015), 58 (1), 96-110CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. IRAK4, a serine/threonine kinase, plays a key role in both inflammation and oncol. diseases. Herein, we summarize the compelling biol. surrounding the IRAK4 signaling node in disease, review key structural features of IRAK4 including selectivity challenges, and describe efforts to discover clin. viable IRAK4 inhibitors. Finally, a view of knowledge gained and remaining challenges is provided.
- 166Dudhgaonkar, S.; Ranade, S.; Nagar, J.; Subramani, S.; Prasad, D. S.; Karunanithi, P.; Srivastava, R.; Venkatesh, K.; Selvam, S.; Krishnamurthy, P.; Mariappan, T. T.; Saxena, A.; Fan, L.; Stetsko, D. K.; Holloway, D. A.; Li, X.; Zhu, J.; Yang, W. P.; Ruepp, S.; Nair, S.; Santella, J.; Duncia, J.; Hynes, J.; McIntyre, K. W.; Carman, J. A. Selective IRAK4 inhibition attenuates disease in murine lupus models and demonstrates steroid sparing activity. J. Immunol. 2017, 198, 1308– 1319, DOI: 10.4049/jimmunol.1600583[Crossref], [PubMed], [CAS], Google Scholar166https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtlaitb8%253D&md5=340ba834510cd04eb0e984e212731e17Selective IRAK4 Inhibition Attenuates Disease in Murine Lupus Models and Demonstrates Steroid Sparing ActivityDudhgaonkar, Shailesh; Ranade, Sourabh; Nagar, Jignesh; Subramani, Siva; Prasad, Durga Shiv; Karunanithi, Preethi; Srivastava, Ratika; Venkatesh, Kamala; Selvam, Sabariya; Krishnamurthy, Prasad; Mariappan, T. Thanga; Saxena, Ajay; Fan, Li; Stetsko, Dawn K.; Holloway, Deborah A.; Li, Xin; Zhu, Jun; Yang, Wen-Pin; Ruepp, Stefan; Nair, Satheesh; Santella, Joseph; Duncia, John; Hynes, John; McIntyre, Kim W.; Carman, Julie A.Journal of Immunology (2017), 198 (3), 1308-1319CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)The serine/threonine kinase IL-1R-assocd. kinase (IRAK)4 is a crit. regulator of innate immunity. We have identified BMS-986126, a potent, highly selective inhibitor of IRAK4 kinase activity that demonstrates equipotent activity against multiple MyD88-dependent responses both in vitro and in vivo. BMS-986126 failed to inhibit assays downstream of MyD88-independent receptors, including the TNF receptor and TLR3. Very little activity was seen downstream of TLR4, which can also activate an MyD88-independent pathway. In mice, the compd. inhibited cytokine prodn. induced by injection of several different TLR agonists, including those for TLR2, TLR7, and TLR9. The compd. also significantly suppressed skin inflammation induced by topical administration of the TLR7 agonist imiquimod. BMS-986126 demonstrated robust activity in the MRL/lpr and NZB/NZW models of lupus, inhibiting multiple pathogenic responses. In the MRL/lpr model, robust activity was obsd. with the combination of suboptimal doses of BMS-986126 and prednisolone, suggesting the potential for steroid sparing activity. BMS-986126 also demonstrated synergy with prednisolone in assays of TLR7- and TLR9-induced IFN target gene expression using human PBMCs. Lastly, BMS-986126 inhibited TLR7- and TLR9-dependent responses using cells derived from lupus patients, suggesting that inhibition of IRAK4 has the potential for therapeutic benefit in treating lupus.
- 167Lee, K. L.; Ambler, C. M.; Anderson, D. R.; Boscoe, B. P.; Bree, A. G.; Brodfuehrer, J. I.; Chang, J. S.; Choi, C.; Chung, S.; Curran, K. J.; Day, J. E.; Dehnhardt, C. M.; Dower, K.; Drozda, S. E.; Frisbie, R. K.; Gavrin, L. K.; Goldberg, J. A.; Han, S.; Hegen, M.; Hepworth, D.; Hope, H. R.; Kamtekar, S.; Kilty, I. C.; Lee, A.; Lin, L. L.; Lovering, F. E.; Lowe, M. D.; Mathias, J. P.; Morgan, H. M.; Murphy, E. A.; Papaioannou, N.; Patny, A.; Pierce, B. S.; Rao, V. R.; Saiah, E.; Samardjiev, I. J.; Samas, B. M.; Shen, M. W. H.; Shin, J. H.; Soutter, H. H.; Strohbach, J. W.; Symanowicz, P. T.; Thomason, J. R.; Trzupek, J. D.; Vargas, R.; Vincent, F.; Yan, J.; Zapf, C. W.; Wright, S. W. Discovery of clinical candidate 1-{[(2s,3s,4s)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a potent, selective inhibitor of interleukin-1 receptor associated kinase 4 (IRAK4), by fragment-based drug design. J. Med. Chem. 2017, 60, 5521– 5542, DOI: 10.1021/acs.jmedchem.7b00231[ACS Full Text], [CAS], Google Scholar167https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnslGqu7c%253D&md5=9771ad2d33089f6ef3dba3556536ff1aDiscovery of Clinical Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug DesignLee, Katherine L.; Ambler, Catherine M.; Anderson, David R.; Boscoe, Brian P.; Bree, Andrea G.; Brodfuehrer, Joanne I.; Chang, Jeanne S.; Choi, Chulho; Chung, Seungwon; Curran, Kevin J.; Day, Jacqueline E.; Dehnhardt, Christoph M.; Dower, Ken; Drozda, Susan E.; Frisbie, Richard K.; Gavrin, Lori K.; Goldberg, Joel A.; Han, Seungil; Hegen, Martin; Hepworth, David; Hope, Heidi R.; Kamtekar, Satwik; Kilty, Iain C.; Lee, Arthur; Lin, Lih-Ling; Lovering, Frank E.; Lowe, Michael D.; Mathias, John P.; Morgan, Heidi M.; Murphy, Elizabeth A.; Papaioannou, Nikolaos; Patny, Akshay; Pierce, Betsy S.; Rao, Vikram R.; Saiah, Eddine; Samardjiev, Ivan J.; Samas, Brian M.; Shen, Marina W. H.; Shin, Julia H.; Soutter, Holly H.; Strohbach, Joseph W.; Symanowicz, Peter T.; Thomason, Jennifer R.; Trzupek, John D.; Vargas, Richard; Vincent, Fabien; Yan, Jiangli; Zapf, Christoph W.; Wright, Stephen W.Journal of Medicinal Chemistry (2017), 60 (13), 5521-5542CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topol. in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chem. effort featured the judicious placement of lipophilicity, informed by cocrystal structures with IRAK4 and optimization of ADME properties to deliver clin. candidate I. This compd. benefitted from a 5-unit increase in lipophilic efficiency from the fragment hit, excellent kinase selectivity, and pharmacokinetic properties suitable for oral administration.
- 168Kelly, P. N.; Romero, D. L.; Yang, Y.; Shaffer, A. L., 3rd; Chaudhary, D.; Robinson, S.; Miao, W.; Rui, L.; Westlin, W. F.; Kapeller, R.; Staudt, L. M. Selective interleukin-1 receptor-associated kinase 4 inhibitors for the treatment of autoimmune disorders and lymphoid malignancy. J. Exp. Med. 2015, 212, 2189– 2201, DOI: 10.1084/jem.20151074[Crossref], [PubMed], [CAS], Google Scholar168https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XjtlSgu7s%253D&md5=cf477aff5f649644017cbe5330995a70Selective interleukin-1 receptor-associated kinase 4 inhibitors for the treatment of autoimmune disorders and lymphoid malignancyKelly, Priscilla N.; Romero, Donna L.; Yang, Yibin; Shaffer, Arthur L., III; Chaudhary, Divya; Robinson, Shaughnessy; Miao, Wenyan; Rui, Lixin; Westlin, William F.; Kapeller, Rosana; Staudt, Louis M.Journal of Experimental Medicine (2015), 212 (13), 2189-2201CODEN: JEMEAV; ISSN:1540-9538. (Rockefeller University Press)Pathol. activation of the Toll-like receptor signaling adaptor protein MYD88 underlies many autoimmune and inflammatory disease states. In the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLB CL), the oncogenic MYD88 L265P mutation occurs in 29% of cases, making it the most prevalent activating mutation in this malignancy. IRAK4 kinase accounts for almost all of the biol. functions of MYD88, highlighting IRAK4 as a therapeutic target for diseases driven by aberrant MYD88 signaling. Using innovative structure-based drug design methodologies, we report the development of highly selective and bioavailable small mol. IRAK4 inhibitors, ND-2158 and ND-2110. These small mols. suppressed LPS-induced TNF prodn., alleviated collagen-induced arthritis, and blocked gout formation in mouse models. IRAK4 inhibition promoted killing of ABC DLB CL lines harboring MYD88 L265P, by down-modulating survival signals, including NF-κB and autocrine IL-6/IL-10 engagement of the JAK-STAT3 pathway. In ABC DLB CL xenograft models, IRAK4 inhibition suppressed tumor growth as a single agent, and in combination with the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib or the Bcl-2 inhibitor ABT-199. Our findings support pharmacol. inhibition of IRAK4 as a therapeutic strategy in autoimmune disorders, in a genetically defined population of ABC DLB CL, and possibly other malignancies dependent on aberrant MYD88 signaling.
- 169Scott, J. S.; Degorce, S. L.; Anjum, R.; Culshaw, J.; Davies, R. D. M.; Davies, N. L.; Dillman, K. S.; Dowling, J. E.; Drew, L.; Ferguson, A. D.; Groombridge, S. D.; Halsall, C. T.; Hudson, J. A.; Lamont, S.; Lindsay, N. A.; Marden, S. K.; Mayo, M. F.; Pease, J. E.; Perkins, D. R.; Pink, J. H.; Robb, G. R.; Rosen, A.; Shen, M.; McWhirter, C.; Wu, D. Discovery and optimization of pyrrolopyrimidine inhibitors of interleukin-1 receptor associated kinase 4 (IRAK4) for the treatment of mutant MyD88(L265P) diffuse large B-cell lymphoma. J. Med. Chem. 2017, 60, 10071– 10091, DOI: 10.1021/acs.jmedchem.7b01290[ACS Full Text], [CAS], Google Scholar169https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVOitrjO&md5=9760f425ec33b238a43e1de0ec6d24f1Discovery and Optimization of Pyrrolopyrimidine Inhibitors of Interleukin-1 Receptor Associated Kinase 4 (IRAK4) for the Treatment of Mutant MYD88L265P Diffuse Large B-Cell LymphomaScott, James S.; Degorce, Sebastien L.; Anjum, Rana; Culshaw, Janet; Davies, Robert D. M.; Davies, Nichola L.; Dillman, Keith S.; Dowling, James E.; Drew, Lisa; Ferguson, Andrew D.; Groombridge, Sam D.; Halsall, Christopher T.; Hudson, Julian A.; Lamont, Scott; Lindsay, Nicola A.; Marden, Stacey K.; Mayo, Michele F.; Pease, J. Elizabeth; Perkins, David R.; Pink, Jennifer H.; Robb, Graeme R.; Rosen, Alan; Shen, Minhui; McWhirter, Claire; Wu, DedongJournal of Medicinal Chemistry (2017), 60 (24), 10071-10091CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Herein we report the optimization of a series of pyrrolopyrimidine inhibitors of interleukin-1 receptor assocd. kinase 4 (IRAK4) using x-ray crystal structures and structure based design to identify and optimize our scaffold. Compd. 28 demonstrated a favorable physicochem. and kinase selectivity profile and was identified as a promising in vivo tool with which to explore the role of IRAK4 inhibition in the treatment of mutant MYD88L265P diffuse large B-cell lymphoma (DLBCL). Compd. 28 was shown to be capable of demonstrating inhibition of NF-κB activation and growth of the ABC subtype of DLBCL cell lines in vitro at high concns. but showed greater effects in combination with a BTK inhibitor at lower concns. In vivo, the combination of compd. 28 and ibrutinib led to tumor regression in an ABC-DLBCL mouse model.
- 170Degorce, S. L.; Anjum, R.; Bloecher, A.; Carbajo, R. J.; Dillman, K. S.; Drew, L.; Halsall, C. T.; Lenz, E. M.; Lindsay, N. A.; Mayo, M. F.; Pink, J. H.; Robb, G. R.; Rosen, A.; Scott, J. S.; Xue, Y. Discovery of a series of 5-azaquinazolines as orally efficacious IRAK4 inhibitors targeting MyD88L265P mutant diffuse large B cell lymphoma. J. Med. Chem. 2019, 62, 9918– 9930, DOI: 10.1021/acs.jmedchem.9b01346[ACS Full Text], [CAS], Google Scholar170https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFyitLzE&md5=5029cfe2e62ca9bc3e7e9a0b02ab8cc0Discovery of a Series of 5-Azaquinazolines as Orally Efficacious IRAK4 Inhibitors Targeting MyD88L265P Mutant Diffuse Large B Cell LymphomaDegorce, Sebastien L.; Anjum, Rana; Bloecher, Andrew; Carbajo, Rodrigo J.; Dillman, Keith S.; Drew, Lisa; Halsall, Christopher T.; Lenz, Eva M.; Lindsay, Nicola A.; Mayo, Michele F.; Pink, Jennifer H.; Robb, Graeme R.; Rosen, Alan; Scott, James S.; Xue, YafengJournal of Medicinal Chemistry (2019), 62 (21), 9918-9930CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)In this article, the authors report the discovery of a series of 5-azaquinazolines as selective IRAK4 inhibitors. From modestly potent quinazoline 4, the authors introduced a 5-aza substitution to mask the 4-NH hydrogen bond donor (HBD). This allowed us to substitute the core with a 2-aminopyrazole, which showed large gains in cellular potency despite the addnl. formal HBD. Further optimization led to 6-cyanomethyl-5-azaquinazoline 13, a selective IRAK4 inhibitor which proved efficacious in combination with ibrutinib, while showing very little activity as a single agent up to 100 mg/kg. This contrasted to previously reported IRAK4 inhibitors that exhibited efficacy in the same model as single agents, and was attributed to the enhanced specificity of 13 towards IRAK4.
- 171Nair, S.; Kumar, S. R.; Paidi, V. R.; Sistla, R.; Kantheti, D.; Polimera, S. R.; Thangavel, S.; Mukherjee, A. J.; Das, M.; Bhide, R. S.; Pitts, W. J.; Murugesan, N.; Dudhgoankar, S.; Nagar, J.; Subramani, S.; Mazumder, D.; Carman, J. A.; Holloway, D. A.; Li, X.; Fereshteh, M. P.; Ruepp, S.; Palanisamy, K.; Mariappan, T. T.; Maddi, S.; Saxena, A.; Elzinga, P.; Chimalakonda, A.; Ruan, Q.; Ghosh, K.; Bose, S.; Sack, J.; Yan, C.; Kiefer, S. E.; Xie, D.; Newitt, J. A.; Saravanakumar, S. P.; Rampulla, R. A.; Barrish, J. C.; Carter, P. H.; Hynes, J., Jr Optimization of nicotinamides as potent and selective IRAK4 inhibitors with efficacy in a murine model of psoriasis. ACS Med. Chem. Lett. 2020, 11, 1402– 1409, DOI: 10.1021/acsmedchemlett.0c00082[ACS Full Text], [CAS], Google Scholar171https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtFWrtbnE&md5=b69996de3d735163ea72a58e89778a97Optimization of Nicotinamides as Potent and Selective IRAK4 Inhibitors with Efficacy in a Murine Model of PsoriasisNair, Satheesh; Kumar, Sreekantha Ratna; Paidi, Venkatram Reddy; Sistla, Ramesh; Kantheti, Durgarao; Polimera, Subba Rao; Thangavel, Soodamani; Mukherjee, Amrita Jha; Das, Mitalee; Bhide, Rajeev S.; Pitts, William J.; Murugesan, Natesan; Dudhgoankar, Shailesh; Nagar, Jignesh; Subramani, Siva; Mazumder, Debarati; Carman, Julie A.; Holloway, Deborah A.; Li, Xin; Fereshteh, Mark P.; Ruepp, Stefan; Palanisamy, Kamalavenkatesh; Mariappan, T. Thanga; Maddi, Srinivas; Saxena, Ajay; Elzinga, Paul; Chimalakonda, Anjaneya; Ruan, Qian; Ghosh, Kaushik; Bose, Sucharita; Sack, John; Yan, Chunhong; Kiefer, Susan E.; Xie, Dianlin; Newitt, John A.; Saravanakumar, S. Pon; Rampulla, Richard A.; Barrish, Joel C.; Carter, Percy H.; Hynes, JohnACS Medicinal Chemistry Letters (2020), 11 (7), 1402-1409CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)IRAK4 is an attractive therapeutic target for the treatment of inflammatory conditions. Structure guided optimization of a nicotinamide series of inhibitors has been expanded to explore the IRAK4 front pocket. This has resulted in the identification of compds. such as 12 with improved potency and selectivity. Addnl. 12 demonstrated activity in a pharmacokinetics/pharmacodynamics (PK/PD) model. Further optimization efforts led to the identification of the highly kinome selective 21, which demonstrated a robust PD effect and efficacy in a TLR7 driven model of murine psoriasis.
- 172Rajapaksa, N. S.; Gobbi, A.; Drobnick, J.; Do, S.; Kolesnikov, A.; Liang, J.; Chen, Y.; Sujatha-Bhaskar, S.; Huang, Z.; Brightbill, H.; Francis, R.; Yu, C.; Choo, E. F.; DeMent, K.; Ran, Y.; An, L.; Emson, C.; Maher, J.; Wai, J.; McKenzie, B. S.; Lupardus, P. J.; Zarrin, A. A.; Kiefer, J. R.; Bryan, M. C. Discovery of potent benzolactam IRAK4 inhibitors with robust in vivo activity. ACS Med. Chem. Lett. 2020, 11, 327– 333, DOI: 10.1021/acsmedchemlett.9b00380[ACS Full Text], [CAS], Google Scholar172https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitFeqs7%252FJ&md5=2fd1d26eea65c726e463cbb8591303efDiscovery of Potent Benzolactam IRAK4 Inhibitors with Robust in Vivo ActivityRajapaksa, Naomi S.; Gobbi, Alberto; Drobnick, Joy; Do, Steven; Kolesnikov, Aleksandr; Liang, Jun; Chen, Yongsheng; Sujatha-Bhaskar, Swathi; Huang, Zhiyu; Brightbill, Hans; Francis, Ross; Yu, Christine; Choo, Edna F.; De Ment, Kevin; Ran, Yingqing; An, Le; Emson, Claire; Maher, Jonathan; Wai, John; McKenzie, Brent S.; Lupardus, Patrick J.; Zarrin, Ali A.; Kiefer, James R.; Bryan, Marian C.ACS Medicinal Chemistry Letters (2020), 11 (3), 327-333CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)IRAK4 kinase activity transduces signaling from multiple IL-1Rs and TLRs to regulate cytokines and chemokines implicated in inflammatory diseases. As such, there is high interest in identifying selective IRAK4 inhibitors for the treatment of these disorders. We previously reported the discovery of potent and selective dihydrobenzofuran inhibitors of IRAK4. Subsequent studies, however, showed inconsistent inhibition in disease-relevant pharmacodynamic models. Herein, we describe application of a human whole blood assay to the discovery of a series of benzolactam IRAK4 inhibitors. We identified potent mol. 19 which achieves robust in vivo inhibition of cytokines relevant to human disease.
- 173Beurel, E.; Grieco, S. F.; Jope, R. S. Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases. Pharmacol. Ther. 2015, 148, 114– 131, DOI: 10.1016/j.pharmthera.2014.11.016[Crossref], [PubMed], [CAS], Google Scholar173https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVeisr7J&md5=a6c54e0331492b0b61a9d67b1f07575dGlycogen synthase kinase-3 (GSK3): Regulation, actions, and diseasesBeurel, Eleonore; Grieco, Steven F.; Jope, Richard S.Pharmacology & Therapeutics (2015), 148 (), 114-131CODEN: PHTHDT; ISSN:0163-7258. (Elsevier)A review. Glycogen synthase kinase-3 (GSK3) may be the busiest kinase in most cells, with over 100 known substrates to deal with. How does GSK3 maintain control to selectively phosphorylate each substrate, and why was it evolutionarily favorable for GSK3 to assume such a large responsibility. GSK3 must be particularly adaptable for incorporating new substrates into its repertoire, and we discuss the distinct properties of GSK3 that may contribute to its capacity to fulfill its roles in multiple signaling pathways. The mechanisms regulating GSK3 (predominantly post-translational modifications, substrate priming, cellular trafficking, protein complexes) have been reviewed previously, so here we focus on newly identified complexities in these mechanisms, how each of these regulatory mechanism contributes to the ability of GSK3 to select which substrates to phosphorylate, and how these mechanisms may have contributed to its adaptability as new substrates evolved. The current understanding of the mechanisms regulating GSK3 is reviewed, as are emerging topics in the actions of GSK3, particularly its interactions with receptors and receptor-coupled signal transduction events, and differential actions and regulation of the two GSK3 isoforms, GSK3α and GSK3β. Another remarkable characteristic of GSK3 is its involvement in many prevalent disorders, including psychiatric and neurol. diseases, inflammatory diseases, cancer, and others. We address the feasibility of targeting GSK3 therapeutically, and provide an update of its involvement in the etiol. and treatment of several disorders.
- 174Saraswati, A. P.; Ali Hussaini, S. M.; Krishna, N. H.; Babu, B. N.; Kamal, A. Glycogen synthase kinase-3 and its inhibitors: Potential target for various therapeutic conditions. Eur. J. Med. Chem. 2018, 144, 843– 858, DOI: 10.1016/j.ejmech.2017.11.103[Crossref], [PubMed], [CAS], Google Scholar174https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXksFGmsg%253D%253D&md5=f1c93ccbd2546fd13296744079255b51Glycogen synthase kinase-3 and its inhibitors: Potential target for various therapeutic conditionsSaraswati, A. Prasanth; Ali Hussaini, S. M.; Krishna, Namballa Hari; Babu, Bathini Nagendra; Kamal, AhmedEuropean Journal of Medicinal Chemistry (2018), 144 (), 843-858CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)A review. Glycogen Synthase Kinase-3 (GSK-3) is a serine/threonine kinase which is ubiquitously expressed and is regarded as a regulator for various cellular events and signaling pathways. It exists in two isoforms, GSK-3α and GSK-3β and can phosphorylate a wide range of substrates. Aberrancy in the GSK-3 activity can lead to various diseases like Alzheimer's, diabetes, cancer, neurodegeneration etc., rendering it an attractive target to develop potent and specific inhibitors. The present review focuses on the recent developments in the area of GSK-3 inhibitors and also enlightens its therapeutic applicability in various disease conditions.
- 175Zhang, F.; Phiel, C. J.; Spece, L.; Gurvich, N.; Klein, P. S. Inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3) in response to lithium. Evidence for autoregulation of GSK-3. J. Biol. Chem. 2003, 278, 33067– 33077, DOI: 10.1074/jbc.M212635200[Crossref], [PubMed], [CAS], Google Scholar175https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXms1als78%253D&md5=f464ab443eb5186e14ad9a028bc57c45Inhibitory Phosphorylation of Glycogen Synthase Kinase-3 (GSK-3) in Response to Lithium: EVIDENCE FOR AUTOREGULATION OF GSK-3Zhang, Fang; Phiel, Christopher J.; Spece, Laura; Gurvich, Nadia; Klein, Peter S.Journal of Biological Chemistry (2003), 278 (35), 33067-33077CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Glycogen synthase kinase-3 (GSK-3) is a crit., neg. regulator of diverse signaling pathways. Lithium is a direct inhibitor of GSK-3 and has been widely used to test the putative role of GSK-3 in multiple settings. However, lithium also inhibits other targets, including inositol monophosphatase and structurally related phosphomonoesterases, and thus addnl. approaches are needed to attribute a given biol. effect of lithium to a specific target. For example, lithium is known to increase the inhibitory N-terminal phosphorylation of GSK-3, but the target of lithium responsible for this indirect regulation has not been identified. We have characterized a short peptide derived from the GSK-3 interaction domain of Axin that potently inhibits GSK-3 activity in vitro and in mammalian cells and robustly activates Wnt-dependent transcription, mimicking lithium action. We show here, using the GSK-3 interaction domain peptide, as well as small mol. inhibitors of GSK-3, that lithium induces GSK-3 N-terminal phosphorylation through direct inhibition of GSK-3 itself. Redn. of GSK-3 protein levels, either by RNA interference or by disruption of the mouse GSK-3β gene, causes increased N-terminal phosphorylation of GSK-3, confirming that GSK-3 regulates its own phosphorylation status. Finally, evidence is presented that N-terminal phosphorylation of GSK-3 can be regulated by the GSK-3-dependent protein phosphatase-1 inhibitor-2 complex.
- 176Dominguez, J. M.; Fuertes, A.; Orozco, L.; del Monte-Millan, M.; Delgado, E.; Medina, M. Evidence for irreversible inhibition of glycogen synthase kinase-3β by tideglusib. J. Biol. Chem. 2012, 287, 893– 904, DOI: 10.1074/jbc.M111.306472[Crossref], [PubMed], [CAS], Google Scholar176https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjslyquw%253D%253D&md5=abc515bddc24ed0ceac990b2335c3816Evidence for Irreversible Inhibition of Glycogen Synthase Kinase-3β by TideglusibDominguez, Juan Manuel; Fuertes, Ana; Orozco, Leyre; del Monte-Millan, Maria; Delgado, Elena; Medina, MiguelJournal of Biological Chemistry (2012), 287 (2), 893-904CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Tideglusib is a GSK-3 inhibitor currently in phase II clin. trials for the treatment of Alzheimer disease and progressive supranuclear palsy. Sustained oral administration of the compd. to a variety of animal models decreases Tau hyperphosphorylation, lowers brain amyloid plaque load, improves learning and memory, and prevents neuronal loss. We report here that tideglusib inhibits GSK-3β irreversibly, as demonstrated by the lack of recovery in enzyme function after the unbound drug was removed from the reaction medium and the fact that its dissocn. rate const. is non-significantly different from zero. Such irreversibility may explain the non-competitive inhibition pattern with respect to ATP shown by tideglusib and perhaps other structurally related compds. The replacement of Cys-199 by an Ala residue in the enzyme seems to increase the dissocn. rate, although the drug retains its inhibitory activity with decreased potency and long residence time. In addn., tideglusib failed to inhibit a series of kinases that contain a Cys homologous to Cys-199 in their active site, suggesting that its inhibition of GSK-3β obeys to a specific mechanism and is not a consequence of nonspecific reactivity. Results obtained with [35S]tideglusib do not support unequivocally the existence of a covalent bond between the drug and GSK-3β. The irreversibility of the inhibition and the very low protein turnover rate obsd. for the enzyme are particularly relevant from a pharmacol. perspective and could have significant implications on its therapeutic potential.
- 177Luna-Medina, R.; Cortes-Canteli, M.; Sanchez-Galiano, S.; Morales-Garcia, J. A.; Martinez, A.; Santos, A.; Perez-Castillo, A. NP031112, a thiadiazolidinone compound, prevents inflammation and neurodegeneration under excitotoxic conditions: potential therapeutic role in brain disorders. J. Neurosci. 2007, 27, 5766– 5776, DOI: 10.1523/JNEUROSCI.1004-07.2007[Crossref], [PubMed], [CAS], Google Scholar177https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmsVWnsLs%253D&md5=cce5ea34a1c384eb3c3c17416f4ca440NP031112, a thiadiazolidinone compound, prevents inflammation and neurodegeneration under excitotoxic conditions: potential therapeutic role in brain disordersLuna-Medina, Rosario; Cortes-Canteli, Marta; Sanchez-Galiano, Susana; Morales-Garcia, Jose A.; Martinez, Ana; Santos, Angel; Perez-Castillo, AnaJournal of Neuroscience (2007), 27 (21), 5766-5776CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)Inflammation and neurodegeneration coexist in many acute damage and chronic CNS disorders (e.g., stroke, Alzheimer's disease, Parkinson's disease). A well characterized animal model of brain damage involves administration of kainic acid, which causes limbic seizure activity and subsequent neuronal death, esp. in the CA1 and CA3 pyramidal cells and interneurons in the hilus of the hippocampus. Our previous work demonstrated a potent anti-inflammatory and neuroprotective effect of two thiadiazolidinones compds., NP00111 (2,4-dibenzyl-[1,2,4]thiadiazolidine-3,5-dione) and NP01138 (2-ethyl-4-phenyl-[1,2,4]thiadiazolidine-3,5-dione), in primary cultures of cortical neurons, astrocytes, and microglia. Here, we show that injection of NP031112, a more potent thiadiazolidinone deriv., into the rat hippocampus dramatically reduces kainic acid-induced inflammation, as measured by edema formation using T2-weighted magnetic resonance imaging and glial activation and has a neuroprotective effect in the damaged areas of the hippocampus. Last, NP031112-induced neuroprotection, both in vitro and in vivo, was substantially attenuated by cotreatment with GW9662 (2-chloro-5-nitrobenzanilide), a known antagonist of the nuclear receptor peroxisome proliferator-activated receptor γ, suggesting that the effects of NP031112 can be mediated through activation of this receptor. As such, these findings identify NP031112 as a potential therapeutic agent for the treatment of neurodegenerative disorders.
- 178del Ser, T.; Steinwachs, K. C.; Gertz, H. J.; Andres, M. V.; Gomez-Carrillo, B.; Medina, M.; Vericat, J. A.; Redondo, P.; Fleet, D.; Leon, T. Treatment of Alzheimer’s disease with the GSK-3 inhibitor tideglusib: a pilot study. J. Alzheimer's Dis. 2012, 33, 205– 215, DOI: 10.3233/JAD-2012-120805
- 179Tolosa, E.; Litvan, I.; Hoglinger, G. U.; Burn, D.; Lees, A.; Andres, M. V.; Gomez-Carrillo, B.; Leon, T.; Del Ser, T. A phase 2 trial of the GSK-3 inhibitor tideglusib in progressive supranuclear palsy. Mov. Disord. 2014, 29, 470– 478, DOI: 10.1002/mds.25824[Crossref], [PubMed], [CAS], Google Scholar179https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXlvFSmtL8%253D&md5=4b7899d99427a60b8edae580355a740dA phase 2 trial of the GSK-3 inhibitor tideglusib in progressive supranuclear palsyTolosa, Eduardo; Litvan, Irene; Hoeglinger, Guenter U.; Burn, David; Lees, Andrew; Andres, Maria V.; Gomez-Carrillo, Belen; Leon, Teresa; del Ser, TeodoroMovement Disorders (2014), 29 (4), 470-478CODEN: MOVDEA; ISSN:0885-3185. (Wiley-Blackwell)It is believed that glycogen synthase kinase-3 (GSK-3) hyperphosphorylates tau protein in progressive supranuclear palsy (PSP). The Tau Restoration on PSP (TAUROS) study was a double-blind, placebo-controlled, randomized trial to assess the efficacy, safety, and tolerability of tideglusib, a GSK-3 inhibitor, as potential treatment for PSP. The study enrolled 146 PSP patients with mild-to-moderate disease who were randomized to receive once-daily 600 mg tideglusib, 800 mg tideglusib, or placebo (ratio, 2:2:1) administered orally over 52 wk. The primary endpoint was the change from baseline to week 52 on the PSP rating scale. Secondary endpoints were safety and tolerability of tideglusib, changes in motor function (the Timed Up and Go Test), cognition (Dementia Rating Scale-2, Frontal Assessment Battery, verbal fluency), apathy (Starkstein scale), activities of daily living (Schwab and England scale; Unified Parkinson's Disease Rating Scale, part II), quality of life (EuroQol), and Global Clin. Assessment. Brain atrophy on magnetic resonance imaging and several biomarkers in plasma and cerebrospinal fluid also were examd. No significant differences were detected in the primary or secondary endpoints at week 52 between placebo and either dose of tideglusib. Tideglusib was safe, with the exception of some asymptomatic, transient, and reversible transaminase elevations (mainly alanine aminotransferase) in 9% of patients, and diarrhea in 13% of patients. Tideglusib was generally well tolerated but it did not show clin. efficacy in patients with mild-to-moderate PSP. © 2014 International Parkinson and Movement Disorder Society.
- 180Hoglinger, G. U.; Huppertz, H. J.; Wagenpfeil, S.; Andres, M. V.; Belloch, V.; Leon, T.; Del Ser, T. Tideglusib reduces progression of brain atrophy in progressive supranuclear palsy in a randomized trial. Mov. Disord. 2014, 29, 479– 487, DOI: 10.1002/mds.25815[Crossref], [PubMed], [CAS], Google Scholar180https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cvhtFKruw%253D%253D&md5=e8876397f081e9988acb720e6805b06cTideglusib reduces progression of brain atrophy in progressive supranuclear palsy in a randomized trialHoglinger Gunter U; Huppertz Hans-Jurgen; Wagenpfeil Stefan; Andres Maria V; Belloch Vincente; Leon Teresa; Del Ser TeodoroMovement disorders : official journal of the Movement Disorder Society (2014), 29 (4), 479-87 ISSN:.It is believed that glycogen synthase kinase-3 hyperphosphorylates tau protein in progressive supranuclear palsy (PSP). The Tau Restoration on PSP (TAUROS) trial assessed the glycogen synthase kinase-3 inhibitor tideglusib as potential treatment. For the magnetic resonance imaging (MRI) substudy reported here, we assessed the progression of brain atrophy. TAUROS was a multinational, phase 2, double-blind, placebo-controlled trial in patients with mild-to-moderate PSP who were treated with oral tideglusib (600 mg or 800 mg daily) or with placebo for 1 year. A subset of patients underwent baseline and 52-week MRI. Automated, observer-independent, atlas-based, and mask-based volumetry was done on high-resolution, T1-weighted, three-dimensional data. For primary outcomes, progression of atrophy was compared both globally (brain, cerebrum) and regionally (third ventricle, midbrain, pons) between the active and placebo groups (Bonferroni correction). For secondary outcomes, 15 additional brain structures were explored (Benjamini & Yekutieli correction). In total, MRIs from 37 patient were studied (placebo group, N = 9; tideglusib 600 mg group, N = 19; tideglusib 800 mg group, N = 9). The groups compared well in their demographic characteristics. Clinical results showed no effect of tideglusib over placebo. Progression of atrophy was significantly lower in the active group than in the placebo group for the brain (mean ± standard error of the mean: -1.3% ± 1.4% vs. -3.1% ± 2.3%, respectively), cerebrum (-1.3% ± 1.5% vs. -3.2% ± 2.1%, respectively), parietal lobe (-1.6% ± 1.9% vs. -4.1% ± 3.0%, respectively), and occipital lobe (-0.3% ± 1.8% vs. -2.7% ± 3.2%, respectively). A trend toward reduced atrophy also was observed in the frontal lobe, hippocampus, caudate nucleus, midbrain, and brainstem. In patients with PSP, tideglusib reduced the progression of atrophy in the whole brain, particularly in the parietal and occipital lobes.
- 181Neves, V. C.; Babb, R.; Chandrasekaran, D.; Sharpe, P. T. Promotion of natural tooth repair by small molecule GSK3 antagonists. Sci. Rep. 2017, 7, 39654, DOI: 10.1038/srep39654[Crossref], [PubMed], [CAS], Google Scholar181https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXotlemug%253D%253D&md5=e599a377016cd709e89950d6157b1d4aPromotion of natural tooth repair by small molecule GSK3 antagonistsNeves, Vitor C. M.; Babb, Rebecca; Chandrasekaran, Dhivya; Sharpe, Paul T.Scientific Reports (2017), 7 (), 39654CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)The restoration of dentin lost in deep caries lesions in teeth is a routine and common treatment that involves the use of inorg. cements based on calcium or silicon-based mineral aggregates. Such cements remain in the tooth and fail to degrade and thus normal mineral vol. is never completely restored. Here we describe a novel, biol. approach to dentin restoration that stimulates the natural formation of reparative dentin via the mobilisation of resident stem cells in the tooth pulp. Biodegradable, clin.-approved collagen sponges are used to deliver low doses of small mol. glycogen synthase kinase (GSK-3) antagonists that promote the natural processes of reparative dentin formation to completely restore dentin. Since the carrier sponge is degraded over time, dentin replaces the degraded sponge leading to a complete, effective natural repair. This simple, rapid natural tooth repair process could thus potentially provide a new approach to clin. tooth restoration.
- 182Gray, J. E.; Infante, J. R.; Brail, L. H.; Simon, G. R.; Cooksey, J. F.; Jones, S. F.; Farrington, D. L.; Yeo, A.; Jackson, K. A.; Chow, K. H.; Zamek-Gliszczynski, M. J.; Burris, H. A., 3rd A first-in-human phase I dose-escalation, pharmacokinetic, and pharmacodynamic evaluation of intravenous LY2090314, a glycogen synthase kinase 3 inhibitor, administered in combination with pemetrexed and carboplatin. Invest. New Drugs 2015, 33, 1187– 1196, DOI: 10.1007/s10637-015-0278-7[Crossref], [PubMed], [CAS], Google Scholar182https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsFKnsr3P&md5=432e42751491fdd88a53688888d89909A first-in-human phase I dose-escalation, pharmacokinetic, and pharmacodynamic evaluation of intravenous LY2090314, a glycogen synthase kinase 3 inhibitor, administered in combination with pemetrexed and carboplatinGray, Jhanelle E.; Infante, Jeffrey R.; Brail, Les H.; Simon, George R.; Cooksey, Jennifer F.; Jones, Suzanne F.; Farrington, Daphne L.; Yeo, Adeline; Jackson, Kimberley A.; Chow, Kay H.; Zamek-Gliszczynski, Maciej J.; Burris, Howard A., IIIInvestigational New Drugs (2015), 33 (6), 1187-1196CODEN: INNDDK; ISSN:0167-6997. (Springer)LY2090314 (LY) is a glycogen synthase kinase 3 inhibitor with preclin. efficacy in xenograft models when combined with platinum regimens. A first-in-human phase 1 dose-escalation study evaluated the combination of LY with pemetrexed/carboplatin. Forty-one patients with advanced solid tumors received single-dose LY monotherapy lead-in and 37 patients received LY (10-120 mg) plus pemetrexed/carboplatin (500 mg/m2 and 5-6 AUC, resp.) across 8 dose levels every 21 days. Primary objective was max. tolerated dose (MTD) detn.; secondary endpoints included safety, antitumor activity, pharmacokinetics, and beta-catenin pharmacodynamics. MTD of LY with pemetrexed/carboplatin was 40 mg. Eleven dose-limiting toxicities (DLTs) occurred in ten patients. DLTs during LY monotherapy occurred at ≥40 mg: grade 2 visual disturbance (n = 1) and grade 3/4 peri-infusional thoracic pain during or shortly post infusion (n = 4; chest, upper abdominal, and back pain). Ranitidine was added after de-escalation to 80 mg LY to minimize peri-infusional thoracic pain. Following LY with pemetrexed/carboplatin therapy, DLTs included grade 3/4 thrombocytopenia (n = 4) and grade 4 neutropenia (n = 1). Best overall response by RECIST included 5 confirmed partial responses (non-small cell lung cancer [n = 3], mesothelioma, and breast cancer) and 19 patients having stable disease. Systemic LY exposure was approx. linear over dose range studied. Transient upregulation of beta-catenin measured in peripheral blood mononuclear cells (PBMCs) occurred at 40 mg LY. The initial safety profile of LY2090314 was established. MTD LY dose with pemetrexed/carboplatin is 40 mg IV every 3 wk plus ranitidine. Efficacy of LY plus pemetrexed/carboplatin requires confirmation in randomized trials.
- 183Ramurthy, S.; Pfister, K. B.; Boyce, R. S.; Brown, S. P.; Costales, A. Q.; Desai, M. C.; Fang, E.; Levine, B. H.; Ng, S. C.; Nuss, J. M.; Ring, D. B.; Shafer, C. M.; Shu, W.; Subramanian, S.; Wagman, A. S.; Wang, H.; Bussiere, D. E. Discovery and optimization of novel pyridines as highly potent and selective glycogen synthase kinase 3 inhibitors. Bioorg. Med. Chem. Lett. 2020, 30, 126930, DOI: 10.1016/j.bmcl.2019.126930[Crossref], [PubMed], [CAS], Google Scholar183https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXmt1OjsQ%253D%253D&md5=3586fe892d2283a9096a3c205d214e9aDiscovery and optimization of novel pyridines as highly potent and selective glycogen synthase kinase 3 inhibitorsRamurthy, Savithri; Pfister, Keith B.; Boyce, Rustum S.; Brown, Sean P.; Costales, Abran Q.; Desai, Manoj C.; Fang, Eric; Levine, Barry H.; Ng, Simon C.; Nuss, John M.; Ring, David B.; Shafer, Cynthia M.; Shu, Wei; Subramanian, Sharadha; Wagman, Allan S.; Wang, Haixia; Bussiere, Dirksen E.Bioorganic & Medicinal Chemistry Letters (2020), 30 (4), 126930CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Glycogen synthase kinase-3 plays an essential role in multiple biochem. pathways in the cell, particularly in regards to energy regulation. As such, Glycogen synthase kinase-3 is an attractive target for pharmacol. intervention in a variety of disease states, particularly non-insulin dependent diabetes mellitus. However, due to homol. with other crucial kinases, such as the cyclin-dependent protein kinase CDC2, developing compds. that are both potent and selective is challenging. A novel series of derivs. of 5-nitro-N2-(2-(pyridine-2-ylamino)ethyl)pyridine-2,6-diamine were synthesized and potently inhibit glycogen synthase kinase-3 (GSK3). Potency in the low nanomolar range was obtained along with remarkable selectivity. The compds. activate glycogen synthase in insulin receptor-expressing CHO-IR cells and in primary rat hepatocytes, and have acceptable pharmacokinetics and pharmacodynamics to allow for oral dosing. The x-ray co-crystal structure of human GSK3-β in complex with compd. 1-(6-((2-((6-amino-5-nitropyridin-2-yl)amino)ethyl)amino)-2-(2,4-dichlorophenyl)pyridin-3-yl)-4-methylpiperazin-2-one is reported and provides insights into the structural determinants of the series responsible for its potency and selectivity.
- 184Wagman, A. S.; Boyce, R. S.; Brown, S. P.; Fang, E.; Goff, D.; Jansen, J. M.; Le, V. P.; Levine, B. H.; Ng, S. C.; Ni, Z. J.; Nuss, J. M.; Pfister, K. B.; Ramurthy, S.; Renhowe, P. A.; Ring, D. B.; Shu, W.; Subramanian, S.; Zhou, X. A.; Shafer, C. M.; Harrison, S. D.; Johnson, K. W.; Bussiere, D. E. Synthesis, binding mode, and antihyperglycemic activity of potent and selective (5-imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine inhibitors of Glycogen synthase kinase 3. J. Med. Chem. 2017, 60, 8482– 8514, DOI: 10.1021/acs.jmedchem.7b00922[ACS Full Text], [CAS], Google Scholar184https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1alur3O&md5=f3bc1e9efca1545f9bee29e1bba6cc92Synthesis, Binding Mode, and Antihyperglycemic Activity of Potent and Selective (5-Imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine Inhibitors of Glycogen Synthase Kinase 3Wagman, Allan S.; Boyce, Rustum S.; Brown, Sean P.; Fang, Eric; Goff, Dane; Jansen, Johanna M.; Le, Vincent P.; Levine, Barry H.; Ng, Simon C.; Ni, Zhi-Jie; Nuss, John M.; Pfister, Keith B.; Ramurthy, Savithri; Renhowe, Paul A.; Ring, David B.; Shu, Wei; Subramanian, Sharadha; Zhou, Xiaohui A.; Shafer, Cynthia M.; Harrison, Stephen D.; Johnson, Kirk W.; Bussiere, Dirksen E.Journal of Medicinal Chemistry (2017), 60 (20), 8482-8514CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)In an effort to identify new antidiabetic agents, we have discovered a novel family of (5-imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine analogs which are inhibitors of human glycogen synthase kinase 3 (GSK3). We developed efficient synthetic routes to explore a wide variety of substitution patterns and convergently access a diverse array of analogs. Compd. I (CHIR-911, CT-99021, or CHIR-73911) emerged from an exploration of heterocycles at the C-5 position, Ph groups at C-4, and a variety of differently substituted linker and aminopyridine moieties attached at the C-2 position. These compds. exhibited GSK3 IC50s in the low nanomolar range and excellent selectivity. They activate glycogen synthase in insulin receptor-expressing CHO-IR cells and primary rat hepatocytes. Evaluation of lead compds. I and II (CHIR-611 or CT-98014) in rodent models of type 2 diabetes revealed that single oral doses lowered hyperglycemia within 60 min, enhanced insulin-stimulated glucose transport, and improved glucose disposal without increasing insulin levels.
- 185Luo, G.; Chen, L.; Burton, C. R.; Xiao, H.; Sivaprakasam, P.; Krause, C. M.; Cao, Y.; Liu, N.; Lippy, J.; Clarke, W. J.; Snow, K.; Raybon, J.; Arora, V.; Pokross, M.; Kish, K.; Lewis, H. A.; Langley, D. R.; Macor, J. E.; Dubowchik, G. M. Discovery of isonicotinamides as highly selective, brain penetrable, and orally active Glycogen synthase kinase-3 inhibitors. J. Med. Chem. 2016, 59, 1041– 1051, DOI: 10.1021/acs.jmedchem.5b01550[ACS Full Text], [CAS], Google Scholar185https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xmslertg%253D%253D&md5=d0412c3fe9b430c59f861fa10d3eff79Discovery of Isonicotinamides as Highly Selective, Brain Penetrable, and Orally Active Glycogen Synthase Kinase-3 InhibitorsLuo, Guanglin; Chen, Ling; Burton, Catherine R.; Xiao, Hong; Sivaprakasam, Prasanna; Krause, Carol M.; Cao, Yang; Liu, Nengyin; Lippy, Jonathan; Clarke, Wendy J.; Snow, Kimberly; Raybon, Joseph; Arora, Vinod; Pokross, Matt; Kish, Kevin; Lewis, Hal A.; Langley, David R.; Macor, John E.; Dubowchik, Gene M.Journal of Medicinal Chemistry (2016), 59 (3), 1041-1051CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)GSK-3 is a serine/threonine kinase that has numerous substrates. Many of these proteins are involved in the regulation of diverse cellular functions, including metab., differentiation, proliferation, and apoptosis. Inhibition of GSK-3 may be useful in treating a no. of diseases including Alzheimer's disease (AD), type II diabetes, mood disorders, and some cancers, but the approach poses significant challenges. Here, the authors present a class of isonicotinamides, e.g. I [R = F, Cl] that are potent, highly kinase-selective GSK-3 inhibitors, the members of which demonstrated oral activity in a triple-transgenic mouse model of AD. The remarkably high kinase selectivity and straightforward synthesis of these compds. bode well for their further exploration as tool compds. and therapeutics.
- 186Griebel, G.; Stemmelin, J.; Lopez-Grancha, M.; Boulay, D.; Boquet, G.; Slowinski, F.; Pichat, P.; Beeske, S.; Tanaka, S.; Mori, A.; Fujimura, M.; Eguchi, J. The selective GSK3 inhibitor, SAR502250, displays neuroprotective activity and attenuates behavioral impairments in models of neuropsychiatric symptoms of Alzheimer’s disease in rodents. Sci. Rep. 2019, 9, 18045, DOI: 10.1038/s41598-019-54557-5[Crossref], [PubMed], [CAS], Google Scholar186https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlWkur7E&md5=3573c37862802bb661aa83750529be88The selective GSK3 inhibitor, SAR502250, displays neuroprotective activity and attenuates behavioral impairments in models of neuropsychiatric symptoms of Alzheimer's disease in rodentsGriebel, Guy; Stemmelin, Jeanne; Lopez-Grancha, Mati; Boulay, Denis; Boquet, Gerald; Slowinski, Franck; Pichat, Philippe; Beeske, Sandra; Tanaka, Shinji; Mori, Akiko; Fujimura, Masatake; Eguchi, JunichiScientific Reports (2019), 9 (1), 18045CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)Glycogen synthase kinase 3 (GSK3) has been identified as a promising target for the treatment of Alzheimer's disease (AD), where abnormal activation of this enzyme has been assocd. with hyperphosphorylation of tau proteins. This study describes the effects of the selective GSK3 inhibitor, SAR502250, in models of neuroprotection and neuropsychiatric symptoms (NPS) assocd. with AD. In P301L human tau transgenic mice, SAR502250 attenuated tau hyperphosphorylation in the cortex and spinal cord. SAR502250 prevented the increase in neuronal cell death in rat embryonic hippocampal neurons following application of the neurotoxic peptide, Aβ25-35. In behavioral studies, SAR502250 improved the cognitive deficit in aged transgenic APP(SW)/Tau(VLW) mice or in adult mice after infusion of Aβ 25-35. It attenuated aggression in the mouse defense test battery and improved depressive-like state of mice in the chronic mild stress procedure after 4 wk of treatment. Moreover, SAR502250 decreased hyperactivity produced by psychostimulants. In contrast, the drug failed to modify anxiety-related behaviors or sensorimotor gating deficit. This profile confirms the neuroprotective effects of GSK3 inhibitors and suggests an addnl. potential in the treatment of some NPS assocd. with AD.
- 187Liang, S. H.; Chen, J. M.; Normandin, M. D.; Chang, J. S.; Chang, G. C.; Taylor, C. K.; Trapa, P.; Plummer, M. S.; Para, K. S.; Conn, E. L.; Lopresti-Morrow, L.; Lanyon, L. F.; Cook, J. M.; Richter, K. E.; Nolan, C. E.; Schachter, J. B.; Janat, F.; Che, Y.; Shanmugasundaram, V.; Lefker, B. A.; Enerson, B. E.; Livni, E.; Wang, L.; Guehl, N. J.; Patnaik, D.; Wagner, F. F.; Perlis, R.; Holson, E. B.; Haggarty, S. J.; El Fakhri, G.; Kurumbail, R. G.; Vasdev, N. Discovery of a highly selective Glycogen synthase kinase-3 inhibitor (PF-04802367) that modulates tau phosphorylation in the brain: translation for PET neuroimaging. Angew. Chem., Int. Ed. 2016, 55, 9601– 9605, DOI: 10.1002/anie.201603797[Crossref], [PubMed], [CAS], Google Scholar187https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtV2itLbF&md5=83a1bfbe16022e6cc30445c2afbab0a1Discovery of a Highly Selective Glycogen Synthase Kinase-3 Inhibitor (PF-04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET NeuroimagingLiang, Steven H.; Chen, Jinshan Michael; Normandin, Marc D.; Chang, Jeanne S.; Chang, George C.; Taylor, Christine K.; Trapa, Patrick; Plummer, Mark S.; Para, Kimberly S.; Conn, Edward L.; Lopresti-Morrow, Lori; Lanyon, Lorraine F.; Cook, James M.; Richter, Karl E. G.; Nolan, Charlie E.; Schachter, Joel B.; Janat, Fouad; Che, Ye; Shanmugasundaram, Veerabahu; Lefker, Bruce A.; Enerson, Bradley E.; Livni, Elijahu; Wang, Lu; Guehl, Nicolas J.; Patnaik, Debasis; Wagner, Florence F.; Perlis, Roy; Holson, Edward B.; Haggarty, Stephen J.; El Fakhri, Georges; Kurumbail, Ravi G.; Vasdev, NeilAngewandte Chemie, International Edition (2016), 55 (33), 9601-9605CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Glycogen synthase kinase-3 (GSK-3) regulates multiple cellular processes in diabetes, oncol., and neurol. N-(3-(1H-1,2,4-triazol-1-yl)propyl)-5-(3-chloro-4-methoxyphenyl)oxazole-4-carboxamide (PF-04802367 or PF-367) has been identified as a highly potent inhibitor, which is among the most selective antagonists of GSK-3 to date. Its efficacy was demonstrated in modulation of tau phosphorylation in vitro and in vivo. Whereas the kinetics of PF-367 binding in brain tissues are too fast for an effective therapeutic agent, the pharmacokinetic profile of PF-367 is ideal for discovery of radiopharmaceuticals for GSK-3 in the central nervous system. A 11C-isotopologue of PF-367 was synthesized and preliminary PET imaging studies in non-human primates confirmed that we have overcome the two major obstacles for imaging GSK-3, namely, reasonable brain permeability and displaceable binding.
- 188Furlotti, G.; Alisi, M. A.; Cazzolla, N.; Dragone, P.; Durando, L.; Magaro, G.; Mancini, F.; Mangano, G.; Ombrato, R.; Vitiello, M.; Armirotti, A.; Capurro, V.; Lanfranco, M.; Ottonello, G.; Summa, M.; Reggiani, A. Hit optimization of 5-substituted-N-(piperidin-4-ylmethyl)-1H-indazole-3-carboxamides: potent Glycogen synthase kinase-3 (GSK-3) inhibitors with in vivo activity in model of mood disorders. J. Med. Chem. 2015, 58, 8920– 8937, DOI: 10.1021/acs.jmedchem.5b01208[ACS Full Text], [CAS], Google Scholar188https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1OqtLbP&md5=9a62da8ef7a7ca4e4b6ff046c0ba1df6Hit Optimization of 5-Substituted-N-(piperidin-4-ylmethyl)-1H-indazole-3-carboxamides: Potent Glycogen Synthase Kinase-3 (GSK-3) Inhibitors with in Vivo Activity in Model of Mood DisordersFurlotti, Guido; Alisi, Maria Alessandra; Cazzolla, Nicola; Dragone, Patrizia; Durando, Lucia; Magaro, Gabriele; Mancini, Francesca; Mangano, Giorgina; Ombrato, Rosella; Vitiello, Marco; Armirotti, Andrea; Capurro, Valeria; Lanfranco, Massimiliano; Ottonello, Giuliana; Summa, Maria; Reggiani, AngeloJournal of Medicinal Chemistry (2015), 58 (22), 8920-8937CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Novel treatments for bipolar disorder with improved efficacy and broader spectrum of activity are urgently needed. Glycogen synthase kinase 3β (GSK-3β) has been suggested to be a key player in the pathophysiol. of bipolar disorder. A series of novel GSK-3β inhibitors having the common N-[(1-alkylpiperidin-4-yl)methyl]-1H-indazole-3-carboxamide scaffold were prepd. taking advantage of an X-ray cocrystal structure of compd. 5 with GSK-3β. We probed different substitutions at the indazole 5-position and at the piperidine-nitrogen to obtain potent ATP-competitive GSK-3β inhibitors with good cell activity. Among the compds. assessed in the in vivo PK expts., 14i showed, after i.p. dosing, encouraging plasma PK profile and brain exposure, as well as efficacy in a mouse model of mania. Compd. 14i was selected for further in vitro/in vivo pharmacol. evaluation, in order to elucidate the use of ATP-competitive GSK-3β inhibitors as new tools in the development of new treatments for mood disorders.
- 189Palomo, V.; Perez, D. I.; Roca, C.; Anderson, C.; Rodriguez-Muela, N.; Perez, C.; Morales-Garcia, J. A.; Reyes, J. A.; Campillo, N. E.; Perez-Castillo, A. M.; Rubin, L. L.; Timchenko, L.; Gil, C.; Martinez, A. Subtly modulating Glycogen synthase kinase 3β: allosteric inhibitor development and their potential for the treatment of chronic diseases. J. Med. Chem. 2017, 60, 4983– 5001, DOI: 10.1021/acs.jmedchem.7b00395[ACS Full Text], [CAS], Google Scholar189https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXos1SgurY%253D&md5=858ba99deb166b43a488c1141c40ff63Subtly Modulating Glycogen Synthase Kinase 3 β: Allosteric Inhibitor Development and Their Potential for the Treatment of Chronic DiseasesPalomo, Valle; Perez, Daniel I.; Roca, Carlos; Anderson, Cara; Rodriguez-Muela, Natalia; Perez, Concepcion; Morales-Garcia, Jose A.; Reyes, Julio A.; Campillo, Nuria E.; Perez-Castillo, Ana M.; Rubin, Lee L.; Timchenko, Lubov; Gil, Carmen; Martinez, AnaJournal of Medicinal Chemistry (2017), 60 (12), 4983-5001CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Glycogen synthase kinase 3β (GSK-3β) is a central target in several unmet diseases. To increase the specificity of GSK-3β inhibitors in chronic treatments, we developed small mols. allowing subtle modulation of GSK-3β activity. Design synthesis, structure-activity relationships, and binding mode of quinoline-3-carbohydrazide derivs. as allosteric modulators of GSK-3β are presented here. Furthermore, we show how allosteric binders may overcome the β-catenin side effects assocd. with strong GSK-3β inhibition. The therapeutic potential of some of these modulators has been tested in human samples from patients with congenital myotonic dystrophy type 1 (CDM1) and spinal muscular atrophy (SMA) patients. We found that compd. I (R1 = 6-Br, R2 = Et, R3 = C11H23) improves delayed myogenesis in CDM1 myoblasts, while compds. I (R1 = H, 6-Br, R2 = Et, R3 = C11H23) have neuroprotective properties in SMA-derived cells. These findings suggest that the allosteric modulators of GSK-3β may be used for future development of drugs for DM1, SMA, and other chronic diseases where GSK-3β inhibition exhibits therapeutic effects.
- 190Wagner, F. F.; Bishop, J. A.; Gale, J. P.; Shi, X.; Walk, M.; Ketterman, J.; Patnaik, D.; Barker, D.; Walpita, D.; Campbell, A. J.; Nguyen, S.; Lewis, M.; Ross, L.; Weiwer, M.; An, W. F.; Germain, A. R.; Nag, P. P.; Metkar, S.; Kaya, T.; Dandapani, S.; Olson, D. E.; Barbe, A. L.; Lazzaro, F.; Sacher, J. R.; Cheah, J. H.; Fei, D.; Perez, J.; Munoz, B.; Palmer, M.; Stegmaier, K.; Schreiber, S. L.; Scolnick, E.; Zhang, Y. L.; Haggarty, S. J.; Holson, E. B.; Pan, J. Q. Inhibitors of Glycogen synthase kinase 3 with exquisite kinome-wide selectivity and their functional effects. ACS Chem. Biol. 2016, 11, 1952– 1963, DOI: 10.1021/acschembio.6b00306[ACS Full Text], [CAS], Google Scholar190https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFemtr7I&md5=2cfb60c9c1936e5ef9986842aedf473fInhibitors of Glycogen Synthase Kinase 3 with Exquisite Kinome-Wide Selectivity and Their Functional EffectsWagner, Florence F.; Bishop, Joshua A.; Gale, Jennifer P.; Shi, Xi; Walk, Michelle; Ketterman, Joshua; Patnaik, Debasis; Barker, Doug; Walpita, Deepika; Campbell, Arthur J.; Nguyen, Shannon; Lewis, Michael; Ross, Linda; Weiwer, Michel; An, W. Frank; Germain, Andrew R.; Nag, Partha P.; Metkar, Shailesh; Kaya, Taner; Dandapani, Sivaraman; Olson, David E.; Barbe, Anne-Laure; Lazzaro, Fanny; Sacher, Joshua R.; Cheah, Jaime H.; Fei, David; Perez, Jose; Munoz, Benito; Palmer, Michelle; Stegmaier, Kimberly; Schreiber, Stuart L.; Scolnick, Edward; Zhang, Yan-Ling; Haggarty, Stephen J.; Holson, Edward B.; Pan, Jen Q.ACS Chemical Biology (2016), 11 (7), 1952-1963CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)The mood stabilizer lithium, the first-line treatment for bipolar disorder, is hypothesized to exert its effects through direct inhibition of glycogen synthase kinase 3 (GSK3) and indirectly by increasing GSK3's inhibitory serine phosphorylation. GSK3 comprises two highly similar paralogs, GSK3α and GSK3β, which are key regulatory kinases in the canonical Wnt pathway. GSK3 stands as a nodal target within this pathway and is an attractive therapeutic target for multiple indications. Despite being an active field of research for the past 20 years, many GSK3 inhibitors demonstrate either poor to moderate selectivity vs. the broader human kinome or physicochem. properties unsuitable for use in in vitro systems or in vivo models. A nonconventional anal. of data from a GSK3β inhibitor high-throughput screening campaign, which excluded known GSK3 inhibitor chemotypes, led to the discovery of a novel pyrazolo-tetrahydroquinolinone scaffold with unparalleled kinome-wide selectivity for the GSK3 kinases. Taking advantage of an uncommon tridentate interaction with the hinge region of GSK3, we developed highly selective and potent GSK3 inhibitors, BRD1652 and BRD0209, which demonstrated in vivo efficacy in a dopaminergic signaling paradigm modeling mood-related disorders. These new chem. probes open the way for exclusive analyses of the function of GSK3 kinases in multiple signaling pathways involved in many prevalent disorders.
- 191Goldstein, D. M.; Kuglstatter, A.; Lou, Y.; Soth, M. J. Selective p38α inhibitors clinically evaluated for the treatment of chronic inflammatory disorders. J. Med. Chem. 2010, 53, 2345– 2353, DOI: 10.1021/jm9012906[ACS Full Text], [CAS], Google Scholar191https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsV2htb%252FM&md5=6bd2bae9fa21fbb56b3e3600aa460580Selective p38α Inhibitors Clinically Evaluated for the Treatment of Chronic Inflammatory DisordersGoldstein, David M.; Kuglstatter, Andreas; Lou, Yan; Soth, Michael J.Journal of Medicinal Chemistry (2010), 53 (6), 2345-2353CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. This Perspective will summarize key learnings from over 15 years of industrial experience with p38 alpha as a drug target, with a focus on the rational design of highly selective small mol. inhibitors, followed by a discussion of data for examples that have entered into or are recruiting for phase 2 clin. studies. To date, these results have been disappointing. We conclude that p38α inhibition alone is unlikely to be a successful strategy toward treating chronic inflammatory disorders.
- 192Liu, C.; Lin, J.; Wrobleski, S. T.; Lin, S.; Hynes, J.; Wu, H.; Dyckman, A. J.; Li, T.; Wityak, J.; Gillooly, K. M.; Pitt, S.; Shen, D. R.; Zhang, R. F.; McIntyre, K. W.; Salter-Cid, L.; Shuster, D. J.; Zhang, H.; Marathe, P. H.; Doweyko, A. M.; Sack, J. S.; Kiefer, S. E.; Kish, K. F.; Newitt, J. A.; McKinnon, M.; Dodd, J. H.; Barrish, J. C.; Schieven, G. L.; Leftheris, K. Discovery of 4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo[1,2-f][ 1,2,4]triazine-6-carboxamide (BMS-582949), a clinical p38α MAP kinase inhibitor for the treatment of inflammatory diseases. J. Med. Chem. 2010, 53, 6629– 6639, DOI: 10.1021/jm100540x[ACS Full Text], [CAS], Google Scholar192https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtV2ktLjM&md5=265713fe6a3e7af415e7b8ea3359f384Discovery of 4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo[1,2-f][1,2,4]triazine-6-carboxamide (BMS-582949), a Clinical p38α MAP Kinase Inhibitor for the Treatment of Inflammatory DiseasesLiu, Chunjian; Lin, James; Wrobleski, Stephen T.; Lin, Shuqun; Hynes, John, Jr.; Wu, Hong; Dyckman, Alaric J.; Li, Tianle; Wityak, John; Gillooly, Kathleen M.; Pitt, Sidney; Shen, Ding Ren; Zhang, Rosemary F.; McIntyre, Kim W.; Salter-Cid, Luisa; Shuster, David J.; Zhang, Hongjian; Marathe, Punit H.; Doweyko, Arthur M.; Sack, John S.; Kiefer, Susan E.; Kish, Kevin F.; Newitt, John A.; McKinnon, Murray; Dodd, John H.; Barrish, Joel C.; Schieven, Gary L.; Leftheris, KaterinaJournal of Medicinal Chemistry (2010), 53 (18), 6629-6639CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The discovery and characterization of 7k (BMS-582949), a highly selective p38α MAP kinase inhibitor that is currently in phase II clin. trials for the treatment of rheumatoid arthritis, is described. A key to the discovery was the rational substitution of N-cyclopropyl for N-methoxy in 1a, a previously reported clin. candidate p38α inhibitor. Unlike alkyl and other cycloalkyls, the sp2 character of the cyclopropyl group can confer improved H-bonding characteristics to the directly substituted amide NH. Inhibitor 7k is slightly less active than 1a in the p38α enzymic assay but displays a superior pharmacokinetic profile and, as such, was more effective in both the acute murine model of inflammation and pseudoestablished rat AA model. The binding mode of 7k with p38α was confirmed by X-ray crystallog. anal.
- 193Liu, C.; Lin, J.; Hynes, J.; Wu, H.; Wrobleski, S. T.; Lin, S.; Dhar, T. G.; Vrudhula, V. M.; Sun, J. H.; Chao, S.; Zhao, R.; Wang, B.; Chen, B. C.; Everlof, G.; Gesenberg, C.; Zhang, H.; Marathe, P. H.; McIntyre, K. W.; Taylor, T. L.; Gillooly, K.; Shuster, D. J.; McKinnon, M.; Dodd, J. H.; Barrish, J. C.; Schieven, G. L.; Leftheris, K. Discovery of ((4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methylpyrrolo[1,2-f][1,2,4]triazine-6-carbonyl)(propyl)carbamoyloxy)methyl-2-(4-(phosphonooxy)phenyl)acetate (BMS-751324), a clinical prodrug of p38α MAP kinase inhibitor. J. Med. Chem. 2015, 58, 7775– 7784, DOI: 10.1021/acs.jmedchem.5b00839[ACS Full Text], [CAS], Google Scholar193https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVykt77E&md5=b7b3eb068ea20677400bbd81d8881921Discovery of ((4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methylpyrrolo[1,2-f][1,2,4]triazine-6-carbonyl)(propyl)carbamoyloxy)methyl-2-(4-(phosphonooxy)phenyl)acetate (BMS-751324), a Clinical Prodrug of p38α MAP Kinase InhibitorLiu, Chunjian; Lin, James; Hynes, John; Wu, Hong; Wrobleski, Stephen T.; Lin, Shuqun; Dhar, T. G. Murali; Vrudhula, Vivekananda M.; Sun, Jung-Hui; Chao, Sam; Zhao, Rulin; Wang, Bei; Chen, Bang-Chi; Everlof, Gerry; Gesenberg, Christoph; Zhang, Hongjian; Marathe, Punit H.; McIntyre, Kim W.; Taylor, Tracy L.; Gillooly, Kathleen; Shuster, David J.; McKinnon, Murray; Dodd, John H.; Barrish, Joel C.; Schieven, Gary L.; Leftheris, KaterinaJournal of Medicinal Chemistry (2015), 58 (19), 7775-7784CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)In search for prodrugs to address the issue of pH-dependent soly. and exposure assocd. with I (BMS-582949), a previously disclosed phase II clin. p38α MAP kinase inhibitor, a structurally novel clin. prodrug, II (BMS-751324), featuring a carbamoylmethylene linked promoiety contg. hydroxyphenyl acetic acid (HPA) derived ester and phosphate functionalities, was identified. Prodrug II was not only stable but also water-sol. under both acidic and neutral conditions. It was effectively bioconverted into parent drug I in vivo by alk. phosphatase and esterase in a stepwise manner, providing higher exposure of I compared to its direct administration, esp. within higher dose ranges. In a rat LPS-induced TNFα pharmacodynamic model and a rat adjuvant arthritis model, II demonstrated similar efficacy to I. Most importantly, it was shown in clin. studies that prodrug II was indeed effective in addressing the pH-dependent absorption issue assocd. with I.
- 194Roy, S. M.; Minasov, G.; Arancio, O.; Chico, L. W.; Van Eldik, L. J.; Anderson, W. F.; Pelletier, J. C.; Watterson, D. M. A selective and brain penetrant p38αMAPK inhibitor candidate for neurologic and neuropsychiatric disorders that attenuates neuroinflammation and cognitive dysfunction. J. Med. Chem. 2019, 62, 5298– 5311, DOI: 10.1021/acs.jmedchem.9b00058[ACS Full Text], [CAS], Google Scholar194https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXntleisLs%253D&md5=501c82424ff421416e71b281f7504e21A Selective and Brain Penetrant p38αMAPK Inhibitor Candidate for Neurologic and Neuropsychiatric Disorders That Attenuates Neuroinflammation and Cognitive DysfunctionRoy, Saktimayee M.; Minasov, George; Arancio, Ottavio; Chico, Laura W.; Van Eldik, Linda J.; Anderson, Wayne F.; Pelletier, Jeffrey C.; Watterson, D. MartinJournal of Medicinal Chemistry (2019), 62 (11), 5298-5311CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The p38αMAPK is a serine/threonine protein kinase and a key node in the intracellular signaling networks that transduce and amplify stress signals into physiol. changes. A preponderance of preclin. data and clin. observations established p38αMAPK as a brain drug discovery target involved in neuroinflammatory responses and synaptic dysfunction in multiple degenerative and neuropsychiatric brain disorders. We summarize the discovery of highly selective, brain-penetrant, small mol. p38αMAPK inhibitors that are efficacious in diverse animal models of neurol. disorders. A crystallog. and pharmacoinformatic approach to fragment expansion enabled the discovery of an efficacious hit. The addn. of secondary pharmacol. screens to refinement delivered lead compds. with improved selectivity, appropriate pharmacodynamics, and efficacy. Safety considerations and addnl. secondary pharmacol. screens drove optimization that delivered the drug candidate MW01-18-150SRM (MW150), currently in early stage clin. trials.
- 195Moens, U.; Kostenko, S.; Sveinbjornsson, B. The role of Mitogen-activated protein kinase-activated protein kinases (MAPKAPKs) in inflammation. Genes 2013, 4, 101– 133, DOI: 10.3390/genes4020101[Crossref], [PubMed], [CAS], Google Scholar195https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXmtlGrt7s%253D&md5=3166c5885677dcb50f40bcfa4c37fd3bThe role of mitogen-activated protein kinase-activated protein kinases (MAPKAPKs) in inflammationMoens, Ugo; Kostenko, Sergiy; Sveinbjoernsson, BaldurGenes (2013), 4 (2), 101-133, 33 pp.CODEN: GENEG9; ISSN:2073-4425. (MDPI AG)A review. Mitogen-activated protein kinase (MAPK) pathways are implicated in several cellular processes including proliferation, differentiation, apoptosis, cell survival, cell motility, metab., stress response and inflammation. MAPK pathways transmit and convert a plethora of extracellular signals by three consecutive phosphorylation events involving a MAPK kinase kinase, a MAPK kinase and a MAPK. In turn MAPKs phosphorylate substrates, including other protein kinases referred to as MAPK-activated protein kinases (MAPKAPKs). Eleven mammalian MAPKAPKs have been identified: ribosomal-S6-kinases (RSK1-4), mitogen- and stress-activated kinases (MSK1-2), MAPK-interacting kinases (MNK1-2), MAPKAPK-2 (MK2), MAPKAPK-3 (MK3) and MAPKAPK-5 (MK5). The role of these MAPKAPKs in inflammation will be reviewed.
- 196Gaestel, M. What goes up must come down: molecular basis of MAPKAP kinase 2/3-dependent regulation of the inflammatory response and its inhibition. Biol. Chem. 2013, 394, 1301– 1315, DOI: 10.1515/hsz-2013-0197[Crossref], [PubMed], [CAS], Google Scholar196https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXlvFent7s%253D&md5=76b71ea718a39f3d007aba58e38ce106What goes up must come down: molecular basis of MAPKAP kinase 2/3-dependent regulation of the inflammatory response and its inhibitionGaestel, MatthiasBiological Chemistry (2013), 394 (10), 1301-1315CODEN: BICHF3; ISSN:1431-6730. (Walter de Gruyter GmbH)A review. Inflammation is normally a fast and transient response to microbial invaders or sterile damage and has to be stringently controlled. The closely-related mitogen-activated protein kinase-activated protein kinases MK2 and MK3 are involved in both up- and down-regulation of inflammation in mammals and govern the inflammatory response at different regulatory levels of gene expression and with different kinetics. In conjunction with their activator MAP kinase p38, MK2 and MK3 stimulate the transcription of immediate-early genes including that of the mRNA-binding protein tristetraprolin (TTP). TTP competes with the constitutively expressed protein human antigen R in binding to the mRNA destabilizing adenylate-uridylate -rich element. MK2 and MK3 also regulate the activity of TTP by direct phosphorylation, det. stability and stimulate the translation of cytokine mRNAs. In addn., TTP controls its own re-synthesis via stability and translation of its mRNA in a phosphorylation-dependent manner. This results in a complex scenario of gene expression and guarantees fast up-regulation and intrinsic feedback control of the inflammatory response of macrophages. Inhibition of MK2/3 by small-mol. pharmaceutical inhibitors is an emerging strategy to manipulate the inflammatory response as a therapeutic option. This strategy could display advantages over the direct inhibition of MAP kinase p38.
- 197Fiore, M.; Forli, S.; Manetti, F. Targeting Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2, MK2): medicinal chemistry efforts to lead small molecule inhibitors to clinical trials. J. Med. Chem. 2016, 59, 3609– 3634, DOI: 10.1021/acs.jmedchem.5b01457[ACS Full Text], [CAS], Google Scholar197https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslWlt7rJ&md5=e6cf6b421991135eddd42154f37c3af1Targeting Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAPK2, MK2): Medicinal Chemistry Efforts To Lead Small Molecule Inhibitors to Clinical TrialsFiore, Mario; Forli, Stefano; Manetti, FabrizioJournal of Medicinal Chemistry (2016), 59 (8), 3609-3634CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The p38/MAPK-activated kinase 2 (MK2) pathway is involved in a series of pathol. conditions (inflammation diseases and metastasis) and in the resistance mechanism to antitumor agents. None of the p38 inhibitors entered advanced clin. trials because of their unwanted systemic side effects. For this reason, MK2 was identified as an alternative target to block the pathway but avoiding the side effects of p38 inhibition. However, ATP-competitive MK2 inhibitors suffered from low soly., poor cell permeability, and scarce kinase selectivity. Fortunately, non-ATP-competitive inhibitors of MK2 have been already discovered that allowed circumventing the selectivity issue. These compds. showed the addnl. advantage to be effective at lower concns. in comparison to the ATP-competitive inhibitors. Therefore, although the significant difficulties encountered during the development of these inhibitors, MK2 is still considered as an attractive target to treat inflammation and related diseases to prevent tumor metastasis and to increase tumor sensitivity to chemotherapeutics.
- 198Singh, R. K.; Najmi, A. K. Novel therapeutic potential of Mitogen-activated protein kinase activated protein kinase 2 (MK2) in chronic airway inflammatory disorders. Curr. Drug Targets 2019, 20, 367– 379, DOI: 10.2174/1389450119666180816121323[Crossref], [PubMed], [CAS], Google Scholar198https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisVCrsr8%253D&md5=4d591506737d6ca4033afd2947f5ab57Novel Therapeutic Potential of Mitogen-Activated Protein Kinase Activated Protein Kinase 2 (MK2) in Chronic Airway Inflammatory DisordersSingh, Rakesh Kumar; Najmi, Abul KalamCurrent Drug Targets (2019), 20 (4), 367-379CODEN: CDTUAU; ISSN:1389-4501. (Bentham Science Publishers Ltd.)Objective: The primary focus of this review is to highlight the current and emerging proinflammatory role of MK2 kinase signaling in p38MAPK pathway and to provide a detailed evaluation on the prospects of MK2 inhibition with special emphasis on the etiol. of chronic inflammatory airway diseases, such as asthma, idiopathic pulmonary fibrosis, lung cancer, acute lung injury and acute respiratory distress syndrome. Background: MK2 belongs to serine-threonine kinase family and is activated directly by stress and inflammatory signal through p38MAPK phosphorylation in diverse inflammatory conditions through the Toll-like receptor signaling pathway. MK2 has been thought to be a crit. factor involved in the regulation of synthesis and release of pro-inflammatory (TNF-α, IL-6 and IL-1β, etc.) proteins. Targeted inhibition of MK2 kinase has been shown to significantly reduce the prodn. and release of these cytokine mols. Therefore, MK2 has been identified as an effective strategy (alternative to p38MAPK) to block this pro-inflammatory signaling pathway. Results: The inhibition of MK2 may lead to similar or better efficacy as that of p38 inhibitors, and interestingly avoids the systemic toxicity shown by the p38 inhibitors. Thus, MK2 has been the focus of intense interdisciplinary research and its specific inhibition can be a novel and potential therapeutic strategy for the treatment of chronic airway inflammatory diseases. Conclusion: Promising advancement in understanding and rigorous exploration of the role of MK2 kinase in inflammatory processes may contribute to the development of newer and safer therapy for the treatment of chronic airway inflammatory diseases in the future.
- 199Mourey, R. J.; Burnette, B. L.; Brustkern, S. J.; Daniels, J. S.; Hirsch, J. L.; Hood, W. F.; Meyers, M. J.; Mnich, S. J.; Pierce, B. S.; Saabye, M. J.; Schindler, J. F.; South, S. A.; Webb, E. G.; Zhang, J.; Anderson, D. R. A benzothiophene inhibitor of mitogen-activated protein kinase-activated protein kinase 2 inhibits tumor necrosis factor α production and has oral anti-inflammatory efficacy in acute and chronic models of inflammation. J. Pharmacol. Exp. Ther. 2010, 333, 797– 807, DOI: 10.1124/jpet.110.166173[Crossref], [PubMed], [CAS], Google Scholar199https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmvFClsLg%253D&md5=312670776fbb3fd39fc2247eba48eb6eA benzothiophene inhibitor of mitogen-activated protein kinase-activated protein kinase 2 inhibits tumor necrosis factor α production and has oral anti-inflammatory efficacy in acute and chronic models of inflammationMourey, Robert J.; Burnette, Barry L.; Brustkern, Sarah J.; Daniels, J. Scott; Hirsch, Jeffrey L.; Hood, William F.; Meyers, Marvin J.; Mnich, Stephen J.; Pierce, Betsy S.; Saabye, Matthew J.; Schindler, John F.; South, Sarah A.; Webb, Elizabeth G.; Zhang, Jian; Anderson, David R.Journal of Pharmacology and Experimental Therapeutics (2010), 333 (3), 797-807CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)Activation of the p38 kinase pathway in immune cells leads to the transcriptional and translational regulation of proinflammatory cytokines. Mitogen-activated protein kinase-activated protein kinase 2 (MK2), a direct downstream substrate of p38 kinase, regulates lipopolysaccharide (LPS)-stimulated tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) prodn. through modulating the stability and translation of these mRNAs. Developing small-mol. inhibitors of MK2 may yield anti-inflammatory efficacy with a different safety profile relative to p38 kinase inhibitors. This article describes the pharmacol. properties of a benzothiophene MK2 inhibitor, PF-3644022 [(10R)-10-methyl-3-(6-methylpyridin-3-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one]. PF-3644022 is a potent freely reversible ATP-competitive compd. that inhibits MK2 activity (Ki = 3 nM) with good selectivity when profiled against 200 human kinases. In the human U937 monocytic cell line or peripheral blood mononuclear cells, PF-3644022 potently inhibits TNFα prodn. with similar activity (IC50 = 160 nM). PF-3644022 blocks TNFα and IL-6 prodn. in LPS-stimulated human whole blood with IC50 values of 1.6 and 10.3 μM, resp. Inhibition of TNFα in U937 cells and blood correlates closely with inhibition of phospho-heat shock protein 27, a target biomarker of MK2 activity. PF-3644022 displays good pharmacokinetic parameters in rats and is orally efficacious in both the rat acute LPS-induced TNFα model and the chronic streptococcal cell wall-induced arthritis model. Dose-dependent inhibition of TNFα prodn. in the acute model and inhibition of paw swelling in the chronic model is obsd. with ED50 values of 6.9 and 20 mg/kg, resp. PF-3644022 efficacy in the chronic inflammation model is strongly correlated with maintaining a Cmin higher than the EC50 measured in the rat LPS-induced TNFα model.
- 200Kosugi, T.; Mitchell, D. R.; Fujino, A.; Imai, M.; Kambe, M.; Kobayashi, S.; Makino, H.; Matsueda, Y.; Oue, Y.; Komatsu, K.; Imaizumi, K.; Sakai, Y.; Sugiura, S.; Takenouchi, O.; Unoki, G.; Yamakoshi, Y.; Cunliffe, V.; Frearson, J.; Gordon, R.; Harris, C. J.; Kalloo-Hosein, H.; Le, J.; Patel, G.; Simpson, D. J.; Sherborne, B.; Thomas, P. S.; Suzuki, N.; Takimoto-Kamimura, M.; Kataoka, K. Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2) as an antiinflammatory target: discovery and in vivo activity of selective pyrazolo[1,5-a]pyrimidine inhibitors using a focused library and structure-based optimization approach. J. Med. Chem. 2012, 55, 6700– 6715, DOI: 10.1021/jm300411k[ACS Full Text], [CAS], Google Scholar200https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpsV2gs7k%253D&md5=78a9e895c0f7a058407de9e344a75458Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAP-K2) as an Antiinflammatory Target: Discovery and in Vivo Activity of Selective Pyrazolo[1,5-a]pyrimidine Inhibitors Using a Focused Library and Structure-Based Optimization ApproachKosugi, Tomomi; Mitchell, Dale R.; Fujino, Aiko; Imai, Minoru; Kambe, Mika; Kobayashi, Shinji; Makino, Hiroaki; Matsueda, Yohei; Oue, Yasuhiro; Komatsu, Kanji; Imaizumi, Keiichiro; Sakai, Yuri; Sugiura, Satoshi; Takenouchi, Osami; Unoki, Gen; Yamakoshi, Yuko; Cunliffe, Vicky; Frearson, Julie; Gordon, Richard; Harris, C. John; Kalloo-Hosein, Heidi; Le, Joelle; Patel, Gita; Simpson, Donald J.; Sherborne, Brad; Thomas, Peter S.; Suzuki, Naotaka; Takimoto-Kamimura, Midori; Kataoka, Ken-ichiroJournal of Medicinal Chemistry (2012), 55 (15), 6700-6715CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A novel class of mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2) inhibitors was discovered through screening a kinase-focused library. A homol. model of MAPKAP-K2 was generated and used to guide the initial SAR studies and to rationalize the obsd. selectivity over CDK2. An x-ray crystal structure of a compd. from the active series bound to cryst. MAPKAP-K2 confirmed the predicted binding mode. This has enabled the discovery of a series of pyrazolo[1,5-a]pyrimidine derivs. showing good in vitro cellular 000 0 potency as anti-TNF-α agents and in vivo efficacy in a mouse model of endotoxin shock.
- 201Velcicky, J.; Schlapbach, A.; Heng, R.; Revesz, L.; Pflieger, D.; Blum, E.; Hawtin, S.; Huppertz, C.; Feifel, R.; Hersperger, R. Modulating ADME properties by fluorination: MK2 inhibitors with improved oral exposure. ACS Med. Chem. Lett. 2018, 9, 392– 396, DOI: 10.1021/acsmedchemlett.8b00098[ACS Full Text], [CAS], Google Scholar201https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXltV2jsLY%253D&md5=6dca69f60838d59b87c90a936682b13aModulating ADME Properties by Fluorination: MK2 Inhibitors with Improved Oral ExposureVelcicky, Juraj; Schlapbach, Achim; Heng, Richard; Revesz, Laszlo; Pflieger, Daniel; Blum, Ernst; Hawtin, Stuart; Huppertz, Christine; Feifel, Roland; Hersperger, ReneACS Medicinal Chemistry Letters (2018), 9 (4), 392-396CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)MAP-activated protein kinase 2 (MK2) plays an important role in the regulation of innate immune response as well as in cell survival upon DNA damage. Despite its potential for the treatment of inflammation and cancer, to date no MK2 low mol. wt. inhibitors have reached the clinic, mainly due to inadequate absorption, distribution, metab., and excretion (ADME) properties. We describe here an approach based on specifically placed fluorine within a recently described pyrrole-based MK2 inhibitor scaffold for manipulation of its physicochem. and ADME properties. While preserving target potency, the novel fluoro-derivs. showed greatly improved permeability as well as enhanced soly. and reduced in vivo clearance leading to significantly increased oral exposure.
- 202Huang, X.; Zhu, X.; Chen, X.; Zhou, W.; Xiao, D.; Degrado, S.; Aslanian, R.; Fossetta, J.; Lundell, D.; Tian, F.; Trivedi, P.; Palani, A. A three-step protocol for lead optimization: quick identification of key conformational features and functional groups in the SAR studies of non-ATP competitive MK2 (MAPKAPK2) inhibitors. Bioorg. Med. Chem. Lett. 2012, 22, 65– 70, DOI: 10.1016/j.bmcl.2011.11.074[Crossref], [PubMed], [CAS], Google Scholar202https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XivVyquw%253D%253D&md5=da2ff998ada081c76f2e9e251af7e109A three-step protocol for lead optimization: Quick identification of key conformational features and functional groups in the SAR studies of non-ATP competitive MK2 (MAPKAPK2) inhibitorsHuang, Xianhai; Zhu, Xiaohong; Chen, Xiao; Zhou, Wei; Xiao, Dong; Degrado, Sylvia; Aslanian, Robert; Fossetta, James; Lundell, Daniel; Tian, Fang; Trivedi, Prashant; Palani, AnandanBioorganic & Medicinal Chemistry Letters (2012), 22 (1), 65-70CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A three-step protocol for SAR development was introduced and applied to the SAR studies of the MK2 inhibitor program. Following this protocol, key conformational features and functional groups for improving MK2 inhibitor activity were quickly identified. Through this effort, the initial gap obsd. between in vitro binding activity and cellular activity in the lead identification stage was very much reduced. Compd. 28 was identified with single digit binding activity (IC50 = 8 nM) and good cellular activity (EC50 = 310 nM). This provides further evidence that non-ATP-competitive binding MK2 inhibitors are feasible by targeting the outside ATP pocket.
- 203Rao, A. U.; Xiao, D.; Huang, X.; Zhou, W.; Fossetta, J.; Lundell, D.; Tian, F.; Trivedi, P.; Aslanian, R.; Palani, A. Facile synthesis of tetracyclic azepine and oxazocine derivatives and their potential as MAPKAP-K2 (MK2) inhibitors. Bioorg. Med. Chem. Lett. 2012, 22, 1068– 1072, DOI: 10.1016/j.bmcl.2011.11.113[Crossref], [PubMed], [CAS], Google Scholar203https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpsFantA%253D%253D&md5=f57cd64420c8735d0f60ad85bdee0b58Facile synthesis of tetracyclic azepine and oxazocine derivatives and their potential as MAPKAP-K2 (MK2) inhibitorsRao, Ashwin U.; Xiao, Dong; Huang, Xianhai; Zhou, Wei; Fossetta, James; Lundell, Dan; Tian, Fang; Trivedi, Prashant; Aslanian, Robert; Palani, AnandanBioorganic & Medicinal Chemistry Letters (2012), 22 (2), 1068-1072CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Facile synthesis of two new series of tetracyclic azepine and oxazocine analogs is described. These analogs were evaluated for their potential as MAPKAP-K2 (MK2) inhibitors and several, e.g., I and II, were found to be potent at inhibiting MK2 with a non-ATP competitive binding mode.
- 204Huang, E. J.; Reichardt, L. F. Trk receptors: roles in neuronal signal transduction. Annu. Rev. Biochem. 2003, 72, 609– 642, DOI: 10.1146/annurev.biochem.72.121801.161629[Crossref], [PubMed], [CAS], Google Scholar204https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXntFSgtbo%253D&md5=939bf60802da0a203c2e0d8585e28dd9Trk receptors: roles in neuronal signal transductionHuang, Eric J.; Reichardt, Louis F.Annual Review of Biochemistry (2003), 72 (), 609-642CODEN: ARBOAW; ISSN:0066-4154. (Annual Reviews Inc.)A review. Trk receptors are a family of 3 receptor tyrosine kinases, each of which can be activated by ≥1 of 4 neurotrophins-nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophins 3 and 4 (NT3 and NT4). Neurotrophin signaling through these receptors regulates cell survival, proliferation, the fate of neural precursors, axon and dendrite growth and patterning, and the expression and activity of functionally important proteins, such as ion channels and neurotransmitter receptors. In the adult nervous system, the Trk receptors regulate synaptic strength and plasticity. The cytoplasmic domains of Trk receptors contain several sites of tyrosine phosphorylation that recruit intermediates in intracellular signaling cascades. As a result, Trk receptor signaling activates several small G proteins, including Ras, Rap-1, and the Cdc-42-Rac-Rho family, as well as pathways regulated by MAP kinase, PI 3-kinase and phospholipase-C-γ (PLC-γ). Trk receptor activation has different consequences in different cells, and the specificity of downstream Trk receptor-mediated signaling is controlled through expression of intermediates in these signaling pathways and membrane trafficking that regulates localization of different signaling constituents. Perhaps the most fascinating aspect of Trk receptor-mediated signaling is its interplay with signaling promoted by the pan-neurotrophin receptor p75NTR. P75NTR activates a distinct set of signaling pathways within cells that are in some instances synergistic and in other instances antagonistic to those activated by Trk receptors. Several of these are proapoptotic but are suppressed by Trk receptor-initiated signaling. P75NTR also influences the conformations of Trk receptors; this modifies ligand-binding specificity and affinity with important developmental consequences.
- 205Yan, W.; Lakkaniga, N. R.; Carlomagno, F.; Santoro, M.; McDonald, N. Q.; Lv, F.; Gunaganti, N.; Frett, B.; Li, H. Y. Insights into current tropomyosin receptor kinase (TRK) inhibitors: development and clinical application. J. Med. Chem. 2019, 62, 1731– 1760, DOI: 10.1021/acs.jmedchem.8b01092[ACS Full Text], [CAS], Google Scholar205https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhs1Khur%252FO&md5=5ce2f8d295cf46f84b46f5890dad0160Insights into Current Tropomyosin Receptor Kinase (TRK) Inhibitors: Development and Clinical ApplicationYan, Wei; Lakkaniga, Naga Rajiv; Carlomagno, Francesca; Santoro, Massimo; McDonald, Neil Q.; Lv, Fengping; Gunaganti, Naresh; Frett, Brendan; Li, Hong-yuJournal of Medicinal Chemistry (2019), 62 (4), 1731-1760CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The use of kinase-directed precision medicine has been heavily pursued since the discovery and development of imatinib. Annually, it is estd. that around ∼20 000 new cases of tropomyosin receptor kinase (TRK) cancers are diagnosed, with the majority of cases exhibiting a TRK genomic rearrangement. In this Perspective, we discuss current development and clin. applications for TRK precision medicine by providing the following: (1) the biol. background and significance of the TRK kinase family, (2) a compilation of known TRK inhibitors and anal. of their cocrystal structures, (3) an overview of TRK clin. trials, and (4) future perspectives for drug discovery and development of TRK inhibitors.
- 206Skerratt, S. E.; Andrews, M.; Bagal, S. K.; Bilsland, J.; Brown, D.; Bungay, P. J.; Cole, S.; Gibson, K. R.; Jones, R.; Morao, I.; Nedderman, A.; Omoto, K.; Robinson, C.; Ryckmans, T.; Skinner, K.; Stupple, P.; Waldron, G. The discovery of a potent, selective, and peripherally restricted pan-Trk inhibitor (PF-06273340) for the treatment of pain. J. Med. Chem. 2016, 59, 10084– 10099, DOI: 10.1021/acs.jmedchem.6b00850[ACS Full Text], [CAS], Google Scholar206https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslWjsbfL&md5=f8c904a92c1716062c217fefe2374ce6The Discovery of a Potent, Selective, and Peripherally Restricted Pan-Trk Inhibitor (PF-06273340) for the Treatment of PainSkerratt, Sarah E.; Andrews, Mark; Bagal, Sharan K.; Bilsland, James; Brown, David; Bungay, Peter J.; Cole, Susan; Gibson, Karl R.; Jones, Russell; Morao, Inaki; Nedderman, Angus; Omoto, Kiyoyuki; Robinson, Colin; Ryckmans, Thomas; Skinner, Kimberly; Stupple, Paul; Waldron, GarethJournal of Medicinal Chemistry (2016), 59 (22), 10084-10099CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The neurotrophin family of growth factors, comprised of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) and neurotrophin 4 (NT4), is implicated in the physiol. of chronic pain. Given the clin. efficacy of anti-NGF monoclonal antibody (mAb) therapies, there is significant interest in the development of small mol. modulators of neurotrophin activity. Neurotrophins signal through the tropomyosin related kinase (Trk) family of tyrosine kinase receptors, hence Trk kinase inhibition represents a potentially "druggable" point of intervention. To deliver the safety profile required for chronic, non-life threatening pain indications, highly kinase-selective Trk inhibitors with minimal brain availability are sought. Herein the authors describe how the use of SBDD, 2D QSAR models and Matched Mol. Pair data in compd. design enabled the delivery of the highly potent, kinase-selective and peripherally restricted clin. candidate PF-06273340.
- 207Loudon, P.; Siebenga, P.; Gorman, D.; Gore, K.; Dua, P.; van Amerongen, G.; Hay, J. L.; Groeneveld, G. J.; Butt, R. P. Demonstration of an anti-hyperalgesic effect of a novel pan-Trk inhibitor PF-06273340 in a battery of human evoked pain models. Br. J. Clin. Pharmacol. 2018, 84, 301– 309, DOI: 10.1111/bcp.13448[Crossref], [PubMed], [CAS], Google Scholar207https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhs1Ois7s%253D&md5=9eeed9ba7e290cf9c3537f30ecd2dc03Demonstration of an anti-hyperalgesic effect of a novel pan-Trk inhibitor PF-06273340 in a battery of human evoked pain modelsLoudon, Peter; Siebenga, Pieter; Gorman, Donal; Gore, Katrina; Dua, Pinky; van Amerongen, Guido; Hay, Justin L.; Groeneveld, Geert Jan; Butt, Richard P.British Journal of Clinical Pharmacology (2018), 84 (2), 301-309CODEN: BCPHBM; ISSN:1365-2125. (Wiley-Blackwell)Inhibitors of nerve growth factor (NGF) reduce pain in several chronic pain indications. NGF signals through tyrosine kinase receptors of the tropomyosin-related kinase (Trk) family and the unrelated p75 receptor. PF-06273340 is a small mol. inhibitor of Trks A, B and C that reduces pain in nonclin. models, and the present study aimed to investigate the pharmacodynamics of this first-in-class mol. in humans. A randomized, double-blind, single-dose, placebo- and active-controlled five-period crossover study was conducted in healthy human subjects (NCT02260947). Subjects received five treatments: PF-06273340 50 mg, PF-06273340 400 mg, pregabalin 300 mg, ibuprofen 600 mg and placebo. The five primary endpoints were the pain detection threshold for the thermal pain tests and the pain tolerance threshold for the cold pressor, elec. stair and pressure pain tests. The trial had predefined decision rules based on 95% confidence that the PF-06273340 effect was better than that of placebo. Twenty subjects entered the study, with 18 completing all five periods. The high dose of PF-06273340 met the decision rules on the UV B skin thermal pain endpoint [least squares (LS) mean vs. placebo: 1.13, 95% confidence interval: 0.64-1.61], but not on the other four primary endpoints. The low dose did not meet the decision criteria for any of the five primary endpoints. Pregabalin (cold pressor and elec. stair tests) and ibuprofen (UVB thermal pain) showed significant analgesic effects on expected endpoints. The study demonstrated, for the first time, the translation of nonclin. effects into man in an inflammatory pain analgesic pharmacodynamic endpoint using a pan-Trk inhibitor.
- 208Wang, T.; Yu, D.; Lamb, M. L. Trk kinase inhibitors as new treatments for cancer and pain. Expert Opin. Ther. Pat. 2009, 19, 305– 319, DOI: 10.1517/13543770902721261[Crossref], [PubMed], [CAS], Google Scholar208https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjslWlu7o%253D&md5=ffc2d3e33102631cac7b89dce7f96a5aTrk kinase inhibitors as new treatments for cancer and painWang, Tao; Yu, Dingwei; Lamb, Michelle L.Expert Opinion on Therapeutic Patents (2009), 19 (3), 305-319CODEN: EOTPEG; ISSN:1354-3776. (Informa Healthcare)A review. Background: Tropomyosin-related kinases (Trks) are a family of receptor tyrosine kinases activated by neurotrophins. Trks play important roles in pain sensation as well as tumor cell growth and survival signaling. Thus, inhibitors of Trk receptor kinases might provide targeted treatments for pain and cancer. Objective: This paper reviews those patent applications since 2002 claiming small-mol. inhibitors of Trk receptor kinases. Methods: Primary literature and patents were searched with SciFinder and Google Scholar. Patents were selected based on their relevance to Trks and were evaluated and representative compds. were listed as examples. Results/conclusion: Several series of Trk inhibitors with excellent in vitro potencies have been reported and a no. of compds. have gone into the clinic. It should be noted that few of these inhibitors are Trk selective, demonstrating that targeting Trk kinases for treatment of pain and/or cancer offers a promising but also challenging approach.
- 209Bagal, S. K.; Andrews, M.; Bechle, B. M.; Bian, J.; Bilsland, J.; Blakemore, D. C.; Braganza, J. F.; Bungay, P. J.; Corbett, M. S.; Cronin, C. N.; Cui, J. J.; Dias, R.; Flanagan, N. J.; Greasley, S. E.; Grimley, R.; James, K.; Johnson, E.; Kitching, L.; Kraus, M. L.; McAlpine, I.; Nagata, A.; Ninkovic, S.; Omoto, K.; Scales, S.; Skerratt, S. E.; Sun, J.; Tran-Dubé, M.; Waldron, G. J.; Wang, F.; Warmus, J. S. Discovery of potent, selective, and peripherally restricted pan-Trk kinase inhibitors for the treatment of pain. J. Med. Chem. 2018, 61, 6779– 6800, DOI: 10.1021/acs.jmedchem.8b00633[ACS Full Text], [CAS], Google Scholar209https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXht1SnurfN&md5=65b55ef6cdd82c44680c6c49310df7b2Discovery of Potent, Selective, and Peripherally Restricted Pan-Trk Kinase Inhibitors for the Treatment of PainBagal, Sharan K.; Andrews, Mark; Bechle, Bruce M.; Bian, Jianwei; Bilsland, James; Blakemore, David C.; Braganza, John F.; Bungay, Peter J.; Corbett, Matthew S.; Cronin, Ciaran N.; Cui, Jingrong Jean; Dias, Rebecca; Flanagan, Neil J.; Greasley, Samantha E.; Grimley, Rachel; James, Kim; Johnson, Eric; Kitching, Linda; Kraus, Michelle L.; McAlpine, Indrawan; Nagata, Asako; Ninkovic, Sacha; Omoto, Kiyoyuki; Scales, Stephanie; Skerratt, Sarah E.; Sun, Jianmin; Tran-Dube, Michelle; Waldron, Gareth J.; Wang, Fen; Warmus, Joseph S.Journal of Medicinal Chemistry (2018), 61 (15), 6779-6800CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Hormones of the neurotrophin family: nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) and neurotrophin 4 (NT4) are known to activate the family of Tropomyosin receptor kinases (TrkA, TrkB, TrkC). Moreover, inhibition of the TrkA kinase pathway in pain has been clin. validated by the NGF antibody tanezumab leading to significant interest in the development of small mol. inhibitors of TrkA. Furthermore, Trk inhibitors having an acceptable safety profile will require minimal brain availability. Herein we discuss the discovery of two potent, selective, peripherally restricted, efficacious and well-tolerated series of pan-Trk inhibitors which successfully delivered three candidate quality compds. I, II and III. All three compds. are predicted to possess low metabolic clearance in human that does not proceed via aldehyde oxidase-catalyzed reactions, thus addressing the potential clearance prediction liability assocd. with our current pan-Trk development candidate PF-06273340.
- 210Stachel, S. J.; Sanders, J. M.; Henze, D. A.; Rudd, M. T.; Su, H.-P.; Li, Y.; Nanda, K. K.; Egbertson, M. S.; Manley, P. J.; Jones, K. L. G.; Brnardic, E. J.; Green, A.; Grobler, J. A.; Hanney, B.; Leitl, M.; Lai, M.-T.; Munshi, V.; Murphy, D.; Rickert, K.; Riley, D.; Krasowska-Zoladek, A.; Daley, C.; Zuck, P.; Kane, S. A.; Bilodeau, M. T. Maximizing diversity from a kinase screen: identification of novel and selective pan-Trk inhibitors for chronic pain. J. Med. Chem. 2014, 57, 5800– 5816, DOI: 10.1021/jm5006429[ACS Full Text], [CAS], Google Scholar210https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXps1SrsLs%253D&md5=f8aaef0b21eb49eed8004fc18f04dff5Maximizing Diversity from a Kinase Screen: Identification of Novel and Selective pan-Trk Inhibitors for Chronic PainStachel, Shawn J.; Sanders, John M.; Henze, Darrell A.; Rudd, Mike T.; Su, Hua-Poo; Li, Yiwei; Nanda, Kausik K.; Egbertson, Melissa S.; Manley, Peter J.; Jones, Kristen L. G.; Brnardic, Edward J.; Green, Ahren; Grobler, Jay A.; Hanney, Barbara; Leitl, Michael; Lai, Ming-Tain; Munshi, Vandna; Murphy, Dennis; Rickert, Keith; Riley, Daniel; Krasowska-Zoladek, Alicja; Daley, Christopher; Zuck, Paul; Kane, Stephanie A.; Bilodeau, Mark T.Journal of Medicinal Chemistry (2014), 57 (13), 5800-5816CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)We have identified several series of small mol. inhibitors of TrkA with unique binding modes. The starting leads were chosen to maximize the structural and binding mode diversity derived from a high throughput screen of our internal compd. collection. These leads were optimized for potency and selectivity employing a structure based drug design approach adhering to the principles of ligand efficiency to maximize binding affinity without overly relying on lipophilic interactions. This endeavor resulted in the identification of several small mol. pan-Trk inhibitor series that exhibit high selectivity for TrkA/B/C vs. a diverse panel of kinases. We have also demonstrated efficacy in both inflammatory and neuropathic pain models upon oral dosing. Herein we describe the identification process, hit-to-lead progression, and binding profiles of these selective pan-Trk kinase inhibitors.
- 211Turk, S.; Merget, B.; Eid, S.; Fulle, S. From cancer to pain target by automated selectivity inversion of a clinical candidate. J. Med. Chem. 2018, 61, 4851– 4859, DOI: 10.1021/acs.jmedchem.8b00140[ACS Full Text], [CAS], Google Scholar211https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpt12hurc%253D&md5=8e29a51d656eb52a41d9abc6fc22ca59From Cancer to Pain Target by Automated Selectivity Inversion of a Clinical CandidateTurk, Samo; Merget, Benjamin; Eid, Sameh; Fulle, SimoneJournal of Medicinal Chemistry (2018), 61 (11), 4851-4859CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Elimination of inadvertent binding is crucial for inhibitor design targeting conserved protein classes like kinases. Compds. in clin. trials provide a rich source for initiating drug design efforts by exploiting such secondary binding events. Considering both aspects, we shifted the selectivity of tozasertib, originally developed against AurA as cancer target, toward the pain target TrkA. First, selectivity-detg. features in binding pockets were identified by fusing interaction grids of several key and off-target conformations. A focused library was subsequently created and prioritized using a multiobjective selection scheme that filters for selective and highly active compds. based on orthogonal methods grounded in computational chem. and machine learning. Eighteen high-ranking compds. were synthesized and exptl. tested. The top-ranked compd. has 10000-fold improved selectivity vs. AurA, nanomolar cellular activity, and is highly selective in a kinase panel. This was achieved in a single round of automated in silico optimization, highlighting the power of recent advances in computer-aided drug design to automate design and selection processes.
- 212Bagal, S. K.; Omoto, K.; Blakemore, D. C.; Bungay, P. J.; Bilsland, J. G.; Clarke, P. J.; Corbett, M. S.; Cronin, C. N.; Cui, J. J.; Dias, R.; Flanagan, N. J.; Greasley, S. E.; Grimley, R.; Johnson, E.; Fengas, D.; Kitching, L.; Kraus, M. L.; McAlpine, I.; Nagata, A.; Waldron, G. J.; Warmus, J. S. Discovery of allosteric, potent, subtype selective, and peripherally restricted TrkA kinase inhibitors. J. Med. Chem. 2019, 62, 247– 265, DOI: 10.1021/acs.jmedchem.8b00280[ACS Full Text], [CAS], Google Scholar212https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXotVahtL4%253D&md5=b83acaa8a60a65cc78aeabe1215cc026Discovery of Allosteric, Potent, Subtype Selective, and Peripherally Restricted TrkA Kinase InhibitorsBagal, Sharan K.; Omoto, Kiyoyuki; Blakemore, David C.; Bungay, Peter J.; Bilsland, James G.; Clarke, Philip J.; Corbett, Matthew S.; Cronin, Ciaran N.; Cui, J. Jean; Dias, Rebecca; Flanagan, Neil J.; Greasley, Samantha E.; Grimley, Rachel; Johnson, Eric; Fengas, David; Kitching, Linda; Kraus, Michelle L.; McAlpine, Indrawan; Nagata, Asako; Waldron, Gareth J.; Warmus, Joseph S.Journal of Medicinal Chemistry (2019), 62 (1), 247-265CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Tropomyosin receptor kinases (TrkA, TrkB, TrkC) are activated by hormones of the neurotrophin family: nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4). Moreover, the NGF antibody tanezumab has provided clin. proof of concept for inhibition of the TrkA kinase pathway in pain leading to significant interest in the development of small mol. inhibitors of TrkA. However, achieving TrkA subtype selectivity over TrkB and TrkC via a Type I and Type II inhibitor binding mode has proven challenging and Type III or Type IV allosteric inhibitors may present a more promising selectivity design approach. Furthermore, TrkA inhibitors with minimal brain availability are required to deliver an appropriate safety profile. Herein, we describe the discovery of a highly potent, subtype selective, peripherally restricted, efficacious, and well-tolerated series of allosteric TrkA inhibitors that culminated in the delivery of candidate quality compd. 23.
- 213Nwosu, L. N.; Mapp, P. I.; Chapman, V.; Walsh, D. A. Blocking the tropomyosin receptor kinase A (TrkA) receptor inhibits pain behaviour in two rat models of osteoarthritis. Ann. Rheum. Dis. 2016, 75, 1246– 1254, DOI: 10.1136/annrheumdis-2014-207203[Crossref], [PubMed], [CAS], Google Scholar213https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXivV2qtrc%253D&md5=a0159f007c97c40704266844aad93ca1Blocking the tropomyosin receptor kinase A (TrkA) receptor inhibits pain behaviour in two rat models of osteoarthritisNwosu, Lilian N.; Mapp, Paul I.; Chapman, Victoria; Walsh, David A.Annals of the Rheumatic Diseases (2016), 75 (6), 1246-1254CODEN: ARDIAO; ISSN:0003-4967. (BMJ Publishing Group)Objectives: Tropomyosin receptor kinase A (TrkA) mediates nociceptor sensitization by nerve growth factor (NGF), but it is unknown whether selective TrkA inhibition will be an effective strategy for treating osteoarthritis (OA) pain. We detd. the effects of a TrkA inhibitor (AR786) on pain behavior, synovitis and joint pathol. in two rat OA models. Methods: Knee OA was induced in rats by intraarticular monosodium-iodoacetate (MIA) injection or meniscal transection (MNX) and compared with saline injected or sham-operated controls. Pain behavior was assessed as wt.-bearing asymmetry and paw withdrawal threshold to punctate stimulation. Oral doses (30 mg/kg) of AR786 or vehicle were administered twice daily in either preventive (day -1 to -27) or treatment (day 14-28) protocols. Effect maintenance was evaluated for 2 wk after treatment discontinuation. Alterations in knee structure (cartilage, subchondral bone and synovium) were examd. by macroscopic visualization of articular surfaces and histopathol. Results: Preventive AR786 treatment inhibited pain behavior development and therapeutic treatment attenuated established pain behavior. Wt.-bearing asymmetry increased 1 wk after treatment discontinuation, but remained less than in vehicle-treated arthritic rats, whereas paw withdrawal thresholds returned to levels of untreated rats within 5 days of treatment discontinuation. AR786 treatment reduced MIA-induced synovitis and did not significantly affect osteochondral pathol. in either model. Conclusions: Blocking NGF activity by inhibiting TrkA reduced pain behavior in two rat models of OA. Analgesia was obsd. both using preventive and treatment protocols, and was sustained after treatment discontinuation. Selective inhibitors of TrkA therefore hold potential for OA pain relief.
- 214Liu, X.; Chan, C.-B.; Qi, Q.; Xiao, G.; Luo, H. R.; He, X.; Ye, K. Optimization of a small Tropomyosin-related kinase B (TrkB) agonist 7,8-dihydroxyflavone active in mouse models of depression. J. Med. Chem. 2012, 55, 8524– 8537, DOI: 10.1021/jm301099x[ACS Full Text], [CAS], Google Scholar214https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlGkurjM&md5=0d018a4f03a45e67728bda926371f844Optimization of a Small Tropomyosin-Related Kinase B (TrkB) Agonist 7,8-Dihydroxyflavone Active in Mouse Models of DepressionLiu, Xia; Chan, Chi-Bun; Qi, Qi; Xiao, Ge; Luo, Hongbo R.; He, Xiaolin; Ye, KeqiangJournal of Medicinal Chemistry (2012), 55 (19), 8524-8537CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Structure-activity relationship study shows that the catechol group in 7,8-dihdyroxyflavone, a selective small TrkB receptor agonist, is crit. for agonistic activity. To improve the poor pharmacokinetic profiles intrinsic to catechol-contg. mols. and to elevate the agonistic effect of the lead compd., we initiated the lead optimization campaign by synthesizing various bioisosteric derivs. Here we show that the optimized 2-methyl-8-(4'-(pyrrolidin-1-yl)phenyl)chromeno[7,8-d]imidazol-6(1H)-one deriv. possesses enhanced TrkB stimulatory activity. Chronic oral administration of this compd. significantly reduces the immobility in forced swim test and tail suspension test, two classical antidepressant behavioral animal models, which is accompanied by robust TrkB activation in hippocampus of mouse brain. Further, in vitro ADMET studies demonstrate that this compd. possesses the improved features compared to the previous lead compd. Hence, this optimized compd. may act as a promising lead candidate for in-depth drug development for treating various neurol. disorders including depression.
- 215Korkmaz, O. T.; Aytan, N.; Carreras, I.; Choi, J. K.; Kowall, N. W.; Jenkins, B. G.; Dedeoglu, A. 7,8-Dihydroxyflavone improves motor performance and enhances lower motor neuronal survival in a mouse model of amyotrophic lateral sclerosis. Neurosci. Lett. 2014, 566, 286– 291, DOI: 10.1016/j.neulet.2014.02.058[Crossref], [PubMed], [CAS], Google Scholar215https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXmt1agu7g%253D&md5=23684b399bba0362747877939e755dcc7,8-Dihydroxyflavone improves motor performance and enhances lower motor neuronal survival in a mouse model of amyotrophic lateral sclerosisKorkmaz, Orhan Tansel; Aytan, Nurgul; Carreras, Isabel; Choi, Ji-Kyung; Kowall, Neil W.; Jenkins, Bruce G.; Dedeoglu, AlpaslanNeuroscience Letters (2014), 566 (), 286-291CODEN: NELED5; ISSN:0304-3940. (Elsevier Ireland Ltd.)Amyotrophic lateral sclerosis (ALS) is an enigmatic neurodegenerative disorder without any effective treatment characterized by loss of motor neurons (MNs) that results in rapidly progressive motor weakness and early death due to respiratory failure. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family known to play a prominent role in the differentiation and survival of MNs. The flavonoid 7,8-dihydroxyflavone (7,8-DHF) is a potent and selective small mol. tyrosine kinase receptor B (TrkB) agonist that mimics the effects of BDNF. In the present study, we evaluated the neuroprotective effects of 7,8-DHF in a transgenic ALS mouse model (SOD1G93A). We found that chronic administration of 7,8-DHF significantly improved motor deficits, and preserved spinal MNs count and dendritic spines in SOD1G93A mice. These data suggest that 7,8-DHF should be considered as a potential therapy for ALS and the other motor neuron diseases.
- 216Koch, P.; Gehringer, M.; Laufer, S. A. Inhibitors of c-Jun N-terminal kinases: an update. J. Med. Chem. 2015, 58, 72– 95, DOI: 10.1021/jm501212r[ACS Full Text], [CAS], Google Scholar216https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvFOhsb%252FN&md5=0d1c32e1463de951c8b47f35882f90abInhibitors of c-Jun N-Terminal Kinases: An UpdateKoch, Pierre; Gehringer, Matthias; Laufer, Stefan A.Journal of Medicinal Chemistry (2015), 58 (1), 72-95CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The c-Jun N-terminal kinases (JNKs) are serine/threonine kinases implicated in the pathogenesis of various diseases. Recent advances in the development of novel inhibitors of JNKs will be reviewed. Significant progress in the design of JNK inhibitors displaying selectivity vs. other kinases has been achieved within the past 4 years. However, the development of isoform selective JNK inhibitors is still an open task.
- 217Swantek, J. L.; Cobb, M. H.; Geppert, T. D. Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) is required for lipopolysaccharide stimulation of tumor necrosis factor α (TNF-α) translation: glucocorticoids inhibit TNF-α translation by blocking JNK/SAPK. Mol. Cell. Biol. 1997, 17, 6274– 6282, DOI: 10.1128/MCB.17.11.6274[Crossref], [PubMed], [CAS], Google Scholar217https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXntVSjsb4%253D&md5=2c62495710ab59a5c07905770ebbf437Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) is required for lipopolysaccharide stimulation of tumor necrosis factor α (TNF-α) translation: glucocorticoids inhibit TNF-α translation by blocking JNK/SAPKSwantek, Jennifer L.; Cobb, Melanie H.; Geppert, Thomas D.Molecular and Cellular Biology (1997), 17 (11), 6274-6282CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)The adverse effects of lipopolysaccharide (LPS) are mediated primarily by TNF-α. TNF-α prodn. by LPS-stimulated macrophages is regulated at the levels of both transcription and translation. It has previously been shown that several mitogen-activated protein kinases (MAPKs) are activated in response to LPS. The authors set out to det. which MAPK signaling pathways are activated in this system and which MAPK pathways are required for TNF-α gene transcription or TNF-α mRNA translation. The authors confirm activation of the MAPK family members extracellular-signal-regulated kinases 1 and 2 (ERK1 and ERK2), p38, and Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), as well as activation of the immediate upstream MAPK activators MAPK/ERK kinases 1 and 4 (MEK1 and MEK4). They also demonstrate that LPS also activates MEK2, MEK3, and MEK6. Furthermore, the authors demonstrate that dexamethasone, which inhibits the prodn. of cytokines, including TNF-α, inhibits LPS induction of JNK/SAPK activity but not that of p38, ERK1 and ERK2, or MEK3, MEK4, or MEK6. Dexamethasone also blocks the sorbitol but not anisomycin stimulation of JNK/SAPK activity. A kinase-defective mutant of SAPKβ, SAPKβ K-A, blocked translation of TNF-α, as detd. by using a TNF-α translational reporting system. Finally, overexpression of wild-type SAPKβ was able to overcome the dexamethasone-induced block of TNF-α translation. Thus, 3 MAPK family members and their upstream activators are stimulated by LPS and JNK/SAPK is required for LPS-induced translation of TNF-α mRNA. A novel mechanism by which dexamethasone inhibits translation of TNF-α is also revealed.
- 218Gaillard, P.; Jeanclaude-Etter, I.; Ardissone, V.; Arkinstall, S.; Cambet, Y.; Camps, M.; Chabert, C.; Church, D.; Cirillo, R.; Gretener, D.; Halazy, S.; Nichols, A.; Szyndralewiez, C.; Vitte, P. A.; Gotteland, J. P. Design and synthesis of the first-generation of novel potent, selective, and in vivo active (benzothiazol-2-yl)acetonitrile inhibitors of the c-Jun N-terminal kinase. J. Med. Chem. 2005, 48, 4596– 4607, DOI: 10.1021/jm0310986[ACS Full Text], [CAS], Google Scholar218https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXkvVGks70%253D&md5=3355648f8e198bfeebb9e505d47f9d77Design and Synthesis of the First Generation of Novel Potent, Selective, and in Vivo Active (Benzothiazol-2-yl)acetonitrile Inhibitors of the c-Jun N-Terminal KinaseGaillard, Pascale; Jeanclaude-Etter, Isabelle; Ardissone, Vittoria; Arkinstall, Steve; Cambet, Yves; Camps, Montserrat; Chabert, Christian; Church, Dennis; Cirillo, Rocco; Gretener, Denise; Halazy, Serge; Nichols, Anthony; Szyndralewiez, Cedric; Vitte, Pierre-Alain; Gotteland, Jean-PierreJournal of Medicinal Chemistry (2005), 48 (14), 4596-4607CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Several lines of evidence support the hypothesis that c-Jun N-terminal kinase (JNKs) plays a crit. role in a wide range of diseases including cell death (apoptosis)-related disorders (neurodegenerative diseases, brain, heart, and renal ischemia, epilepsy) and inflammatory disorders (multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases). Screening of an internal compd. collection for inhibitors of JNK3 led to the identification of (benzothiazol-2-yl)acetonitrile derivs. as potent and selective JNK1, -2, -3 inhibitors. Starting from initial hit I [R = Cl, R1 = Br] (AS007149), the chem. and initial structure-activity relationship (SAR) of this novel and unique kinase inhibitor template were explored. Investigation of the SAR rapidly revealed that the benzothiazol-2-ylacetonitrile pyrimidine core was crucial to retain a good level of potency on rat JNK3. Therefore, I [R = Cl, R1 = H] was further optimized by exploring a no. of distal combinations in place of the chlorine atom. This led to the observation that the presence of an arom. group, two carbons away from the aminopyrimidine moiety and bearing substituents conferring hydrogen bond acceptor (HBA) properties, could improve the potency. Further improvements to the biol. and biopharmaceutical profile of the most promising compds. were performed, resulting in the discovery of I [R = 2-(3-pyridinyl)ethyl, R1 = H] (AS601245). The in vitro and in vivo anti-inflammatory potential of this new JNK inhibitor was investigated and found to demonstrate efficacy per oral route in an exptl. model of rheumatoid arthritis (RA).
- 219Colombo, A.; Bastone, A.; Ploia, C.; Sclip, A.; Salmona, M.; Forloni, G.; Borsello, T. JNK regulates APP cleavage and degradation in a model of Alzheimer’s disease. Neurobiol. Dis. 2009, 33, 518– 525, DOI: 10.1016/j.nbd.2008.12.014[Crossref], [PubMed], [CAS], Google Scholar219https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXitVSjt74%253D&md5=7e7ba36777e13a3bf5430b8be9c1cc14JNK regulates APP cleavage and degradation in a model of Alzheimer's diseaseColombo, Alessio; Bastone, Antonio; Ploia, Cristina; Sclip, Alessandra; Salmona, Mario; Forloni, Gianluigi; Borsello, TizianaNeurobiology of Disease (2009), 33 (3), 518-525CODEN: NUDIEM; ISSN:0969-9961. (Elsevier B.V.)Secretion of Amyloid-beta peptide (Aβ) circulating oligomers and their aggregate forms derived by processing of beta-amyloid precursor protein (APP) are a key event in Alzheimer's disease (AD). We show that phosphorylation of APP on threonine 668 may play a role in APP metab. in H4-APPsw cell line, a degenerative AD model. We proved that JNK plays a fundamental role in this phosphorylation since its specific inhibition, with the JNK inhibitor peptide (D-JNKI1), induced APP degrdn. and prevented APP phosphorylation at T668. This results in a significant drop of βAPPs, Aβ fragments and Aβ circulating oligomers. Moreover the D-JNKI1 treatment produced a switch in the APP metab., since the peptide reduced the rate of the amyloidogenic processing in favor of the non-amyloidogenic one. All together our results suggest an important link between APP metab. and the JNK pathway and contribute to shed light on the mol. signalling pathway of this disease indicating JNK as an innovative target for AD therapy.
- 220Ploia, C.; Antoniou, X.; Sclip, A.; Grande, V.; Cardinetti, D.; Colombo, A.; Canu, N.; Benussi, L.; Ghidoni, R.; Forloni, G.; Borsello, T. JNK plays a key role in tau hyperphosphorylation in Alzheimer’s disease models. J. Alzheimer's Dis. 2011, 26, 315– 329, DOI: 10.3233/JAD-2011-110320[Crossref], [PubMed], [CAS], Google Scholar220https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFeks7fF&md5=2f80e53c135240675ffacf5041278e06JNK Plays a Key Role in Tau Hyperphosphorylation in Alzheimer's Disease ModelsPloia, Cristina; Antoniou, Xanthi; Sclip, Alessandra; Grande, Valentina; Cardinetti, Daniele; Colombo, Alessio; Canu, Nadia; Benussi, Luisa; Ghidoni, Roberta; Forloni, Gianluigi; Borsello, TizianaJournal of Alzheimer's Disease (2011), 26 (2), 315-329CODEN: JADIF9; ISSN:1387-2877. (IOS Press)Alzheimer's disease (AD) is a major clin. concern, and the search for new mols. to combat disease progression remains important. One of the major hallmarks in AD pathogenesis is the hyperphosphorylation of tau and subsequent formation of neurofibrillary tangles. Several kinases are involved in this process. Amongst them, c-Jun N-terminal kinases (JNKs) are activated in AD brains and are also assocd. with the development of amyloid plaques. This study was designed to investigate the contribution of JNK in tau hyperphosphorylation and whether it may represent a potential therapeutic target for the fight against AD. The specific inhibition of JNK by the cell permeable peptide D-JNKI-1 led to a redn. of p-tau at S202/T205 and S422, two established target sites of JNK, in rat neuronal cultures and in human fibroblasts cultures. Similarly, D-JNKI-1 reduced p-tau at S202/T205 in an in vivo model of AD (TgCRND8 mice). Our findings support the fundamental role of JNK in the regulation of tau hyperphosphorylation and subsequently in AD pathogenesis.
- 221Zhou, Q.; Wang, M.; Du, Y.; Zhang, W.; Bai, M.; Zhang, Z.; Li, Z.; Miao, J. Inhibition of c-Jun N-terminal kinase activation reverses Alzheimer disease phenotypes in APPswe/PS1dE9 mice. Ann. Neurol. 2015, 77, 637– 654, DOI: 10.1002/ana.24361[Crossref], [PubMed], [CAS], Google Scholar221https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXlt1WqtLc%253D&md5=0f6ce5cdf905ffc7aea5cb38d90de401Inhibition of c-Jun N-terminal kinase activation reverses Alzheimer disease phenotypes in APPswe/PS1dE9 miceZhou, Qiong; Wang, Man; Du, Ying; Zhang, Wei; Bai, Miao; Zhang, Zhuo; Li, Zhuyi; Miao, JiantingAnnals of Neurology (2015), 77 (4), 637-654CODEN: ANNED3; ISSN:0364-5134. (John Wiley & Sons, Inc.)Objective : Growing evidence indicates that the activation of c-Jun N-terminal kinase (JNK) is implicated in the multiple major pathol. features of Alzheimer disease (AD). However, whether specific inhibition of JNK activation could prevent disease progression in adult transgenic AD models at moderate stage remains unknown. Here we first investigated the potential disease-modifying therapeutic effect of systemic administration of SP600125, a small-mol. JNK-specific inhibitor, in middle-aged APPswe/PS1dE9 mice. Methods : Using behavioral, histol., and biochem. methods, outcomes of SP600125 treatment on neuropathol. and cognitive deficits were studied in APPswe/PS1dE9 mice. Results : Compared with vehicle-treated APPswe/PS1dE9 mice, chronic treatment of SP600125 for 12 wk potently inhibited JNK activation, which resulted in a marked improvement of behavioral measures of cognitive deficits and a dramatic redn. in amyloid plaque burden, β-amyloid prodn., tau hyperphosphorylation, inflammatory responses, and synaptic loss in these transgenic animals. In particular, we found that SP600125 treatment strongly promoted nonamyloidogenic amyloid precursor protein (APP) processing and inhibited amyloidogenic APP processing via regulating APP-cleavage secretase expression (ie, ADAM10, BACE1, and PS1) in APPswe/PS1dE9 mice. Interpretation : Our findings demonstrate that chronic SP600125 treatment is powerfully effective in slowing down disease progression by markedly reducing multiple pathol. features and ameliorating cognitive deficits assocd. with AD. This study highlights the concept that active JNK actually contributes to the development of the disease, and provides crit. preclin. evidence that specific inhibition of JNK activation by SP600125 treatment may be a novel promising disease-modifying therapeutic strategy for the treatment of AD.
- 222Eynott, P. R.; Nath, P.; Leung, S. Y.; Adcock, I. M.; Bennett, B. L.; Chung, K. F. Allergen-induced inflammation and airway epithelial and smooth muscle cell proliferation: role of Jun N-terminal kinase. Br. J. Pharmacol. 2003, 140, 1373– 1380, DOI: 10.1038/sj.bjp.0705569[Crossref], [PubMed], [CAS], Google Scholar222https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhsV2rtQ%253D%253D&md5=ac856cb6e94636a9565a1e8832e3f5baAllergen-induced inflammation and airway epithelial and smooth muscle cell proliferation: Role of Jun N-terminal kinaseEynott, Paul R.; Nath, Puneeta; Leung, Sum-Yee; Adcock, Ian M.; Bennett, Brydon L.; Chung, K. FanBritish Journal of Pharmacology (2003), 140 (8), 1373-1380CODEN: BJPCBM; ISSN:0007-1188. (Nature Publishing Group)1 Chronic cellular inflammation and airway wall remodelling with subepithelial fibrosis and airway smooth muscle (ASM) cell hyperplasia are features of chronic asthma. Jun N-terminal kinase (JNK) may be implicated in these processes by regulating the transcriptional activity of activator protein (AP)-1. 2 The authors examd. the effects of an inhibitor of JNK, SP600125 (anthra [1,9-cd] pyrazole-6 (2 H)-one), in a model of chronic allergic inflammation in the rat. 3 Rats sensitized to ovalbumin (OA) were exposed to OA-aerosol every third day on six occasions and were treated with SP600125 (30 mg kg-1 b.i.d; 360 mg in total) for 12 days, starting after the second through to the sixth OA exposure. The authors measured eosinophilic and T-cell inflammation in the airways, proliferation of ASM cells and epithelial cells by incorporation of bromodeoxyuridine (BrdU), and bronchial responsiveness to acetylcholine. 4 SP600125 significantly reduced the no. of eosinophils and lymphocytes in bronchoalveolar lavage fluid, suppressed eosinophilic and CD2+ T-cell infiltration within the bronchial submucosa, and the increased DNA incorporation in ASM and epithelial cell incorporation. 5 SP600125 did not alter bronchial hyper-responsiveness obsd. after chronic allergen exposure. 6 Pathways regulated by JNK pos. regulate ASM cell proliferation and allergic cellular inflammation following chronic allergen exposure.
- 223Palmer, S. S.; Altan, M.; Denis, D.; Tos, E. G.; Gotteland, J. P.; Osteen, K. G.; Bruner-Tran, K. L.; Nataraja, S. G. Bentamapimod (JNK inhibitor AS602801) induces regression of endometriotic lesions in animal models. Reprod. Sci. 2016, 23, 11– 23, DOI: 10.1177/1933719115600553[Crossref], [PubMed], [CAS], Google Scholar223https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XpvVensrY%253D&md5=f8604d4855f38f0a3888a59cf27f463eBentamapimod (JNK inhibitor AS602801) induces regression of endometriotic lesions in animal modelsPalmer, Stephen S.; Altan, Melis; Denis, Deborah; Tos, Enrico Gillio; Gotteland, Jean-Pierre; Osteen, Kevin G.; Bruner-Tran, Kaylon L.; Nataraja, Selvaraj G.Reproductive Sciences (2016), 23 (1), 11-23CODEN: RSECC3; ISSN:1933-7191. (Sage Publications)Endometriosis is an estrogen (ER)-dependent gynecol. disease caused by the growth of endometrial tissue at extrauterine sites. Current endocrine therapies address the estrogenic aspect of disease and offer some relief from pain but are assocd. with significant side effects. Immune dysfunction is also widely believed to be an underlying contributor to the pathogenesis of this disease. This study evaluated an inhibitor of c-Jun N-terminal kinase, bentamapimod (AS602801), which interrupts immune pathways, in 2 rodent endometriosis models. Treatment of nude mice bearing xenografts biopsied from women with endometriosis (BWE) with 30 mg/kg AS602801 caused 29% regression of lesion. Medroxyprogesterone acetate (MPA) or progesterone (PR) alone did not cause regression of BWE lesions, but combining 10 mg/kg AS602801 with MPA caused 38% lesion regression. In human endometrial organ cultures (from healthy women), treatment with AS602801 or MPA reduced matrix metalloproteinase-3 (MMP-3) release into culture medium. In organ cultures established with BWE, PR or MPA failed to inhibit MMP-3 secretion, whereas AS602801 alone or MPA + AS602801 suppressed MMP-3 prodn. In an autologous rat endometriosis model, AS602801 caused 48% regression of lesions compared to GnRH antagonist Antide (84%). AS602801 reduced inflammatory cytokines in endometriotic lesions, while levels of cytokines in ipsilateral horns were unaffected. Furthermore, AS602801 enhanced natural killer cell activity, without apparent neg. effects on uterus. These results indicate that bentamapimod induced regression of endometriotic lesions in endometriosis rodent animal models without suppressing ER action. c-Jun N-terminal kinase inhibition mediated a comprehensive redn. in cytokine secretion and moreover was able to overcome PR resistance.
- 224Plantevin Krenitsky, V.; Nadolny, L.; Delgado, M.; Ayala, L.; Clareen, S. S.; Hilgraf, R.; Albers, R.; Hegde, S.; D’Sidocky, N.; Sapienza, J.; Wright, J.; McCarrick, M.; Bahmanyar, S.; Chamberlain, P.; Delker, S. L.; Muir, J.; Giegel, D.; Xu, L.; Celeridad, M.; Lachowitzer, J.; Bennett, B.; Moghaddam, M.; Khatsenko, O.; Katz, J.; Fan, R.; Bai, A.; Tang, Y.; Shirley, M. A.; Benish, B.; Bodine, T.; Blease, K.; Raymon, H.; Cathers, B. E.; Satoh, Y. Discovery of CC-930, an orally active anti-fibrotic JNK inhibitor. Bioorg. Med. Chem. Lett. 2012, 22, 1433– 1438, DOI: 10.1016/j.bmcl.2011.12.027[Crossref], [PubMed], [CAS], Google Scholar224https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhslCls7c%253D&md5=fc99284fc784d1649286c95888a94e5eDiscovery of CC-930, an orally active anti-fibrotic JNK inhibitorPlantevin Krenitsky, Veronique; Nadolny, Lisa; Delgado, Mercedes; Ayala, Leticia; Clareen, Steven S.; Hilgraf, Robert; Albers, Ronald; Hegde, Sayee; D'Sidocky, Neil; Sapienza, John; Wright, Jonathan; McCarrick, Meg; Bahmanyar, Sogole; Chamberlain, Philip; Delker, Silvia L.; Muir, Jeff; Giegel, David; Xu, Li; Celeridad, Maria; Lachowitzer, Jeff; Bennett, Brydon; Moghaddam, Mehran; Khatsenko, Oleg; Katz, Jason; Fan, Rachel; Bai, April; Tang, Yang; Shirley, Michael A.; Benish, Brent; Bodine, Tracey; Blease, Kate; Raymon, Heather; Cathers, Brian E.; Satoh, YoshitakaBioorganic & Medicinal Chemistry Letters (2012), 22 (3), 1433-1438CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)In this Letter we describe the discovery of potent, selective, and orally active aminopurine JNK inhibitors. Improving the physico-chem. properties as well as increasing the potency and selectivity of a subseries with rat plasma exposure, led to the identification of four structurally diverse inhibitors. Differentiation based on PK profiles in multiple species as well as activity in a chronic efficacy model led to the identification of 1 (CC-930, I) as a development candidate, which is currently in Phase II clin. trial for IPF.
- 225Kaoud, T. S.; Mitra, S.; Lee, S.; Taliaferro, J.; Cantrell, M.; Linse, K. D.; Van Den Berg, C. L.; Dalby, K. N. Development of JNK2-selective peptide inhibitors that inhibit breast cancer cell migration. ACS Chem. Biol. 2011, 6, 658– 666, DOI: 10.1021/cb200017n[ACS Full Text], [CAS], Google Scholar225https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXkt1Wnu7k%253D&md5=7cf41c3797ada88ab0bdde9a087cfec9Development of JNK2-Selective Peptide Inhibitors That Inhibit Breast Cancer Cell MigrationKaoud, Tamer S.; Mitra, Shreya; Lee, Sunbae; Taliaferro, Juliana; Cantrell, Michael; Linse, Klaus D.; Van Den Berg, Carla L.; Dalby, Kevin N.ACS Chemical Biology (2011), 6 (6), 658-666CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)Despite their lack of selectivity toward c-Jun N-terminal kinase (JNK) isoforms, peptides derived from the JIP (JNK Interacting Protein) scaffolds linked to the cell-penetrating peptide TAT are widely used to investigate JNK-mediated signaling events. To engineer an isoform-selective peptide inhibitor, several JIP-based peptide sequences were designed and tested. A JIP sequence connected through a flexible linker to either the N-terminus of an inverted TAT sequence (JIP10-Δ-TATi) or to a poly arginine sequence (JIP10-Δ-R9) enabled the potent inhibition of JNK2 (IC50 ≈ 90 nM) and exhibited 10-fold selectivity for JNK2 over JNK1 and JNK3. Examn. of both peptides in HEK293 cells revealed a potent ability to inhibit the induction of both JNK activation and c-Jun phosphorylation in cells treated with anisomycin. Notably, Western blot anal. indicates that only a fraction of total JNK must be activated to elicit robust c-Jun phosphorylation. To examine the potential of each peptide to selectively modulate JNK2 signaling in vivo, their ability to inhibit the migration of Polyoma Middle-T Antigen Mammary Tumor (PyVMT) cells was assessed. PyVMTjnk2-/- cells exhibit a lower migration potential compared to PyVMTjnk2+/+ cells, and this migration potential is restored through the overexpression of GFP-JNK2α. Both JIP10-Δ-TATi and JIP10-Δ-R9 inhibit the migration of PyVMTjnk2+/+ cells and PyVMTjnk2-/- cells expressing GFP-JNK2α. However, neither peptide inhibits the migration of PyVMTjnk2-/- cells. A control form of JIP10-Δ-TATi contg. a single leucine to arginine mutation lacks ability to inhibit JNK2 in vitro cell-free and cell-based assays and does not inhibit the migration of PyVMTjnk2+/+ cells. Together, these data suggest that JIP10-Δ-TATi and JIP10-Δ-R9 inhibit the migration of PyVMT cells through the selective inhibition of JNK2. Finally, the mechanism of inhibition of a D-retro-inverso JIP peptide, previously reported to inhibit JNK, was examd. and found to inhibit p38MAPKα in an in vitro cell-free assay with little propensity to inhibit JNK isoforms.
- 226Dou, X.; Huang, H.; Li, Y.; Jiang, L.; Wang, Y.; Jin, H.; Jiao, N.; Zhang, L.; Zhang, L.; Liu, Z. Multistage screening reveals 3-substituted indolin-2-one derivatives as novel and isoform-selective c-jun N-terminal kinase 3 (JNK3) inhibitors: implications to drug discovery for potential treatment of neurodegenerative diseases. J. Med. Chem. 2019, 62, 6645– 6664, DOI: 10.1021/acs.jmedchem.9b00537[ACS Full Text], [CAS], Google Scholar226https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtlamsbbM&md5=ed74af99cc8e89a98874fcf6e9bcdd4eMultistage Screening Reveals 3-Substituted Indolin-2-one Derivatives as Novel and Isoform-Selective c-Jun N-terminal Kinase 3 (JNK3) Inhibitors: Implications to Drug Discovery for Potential Treatment of Neurodegenerative DiseasesDou, Xiaodong; Huang, Huixia; Li, Yibo; Jiang, Lan; Wang, Yanxing; Jin, Hongwei; Jiao, Ning; Zhang, Lihe; Zhang, Liangren; Liu, ZhenmingJournal of Medicinal Chemistry (2019), 62 (14), 6645-6664CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Alzheimer's disease (AD) is one of the most challenging diseases around the world with no effective clin. treatment. Previous studies have suggested c-Jun N-terminal kinase 3 (JNK3) as an attractive therapeutic target for AD. Herein, we report 3-substituted indolin-2-one derivs. as the first isoform-selective JNK3 inhibitors by multistage screening. In this study, comparative structure-based virtual screening was performed, and J30-8 was identified with a half-maximal inhibitory concn. of 40 nM, which exhibited over 2500-fold isoform selectivity and marked kinome-wide selectivity. Further study indicated that 1 μM J30-8 exhibited neuroprotective activity in vitro so as to alleviate the spatial memory impairment in vivo through reducing plaque burden and inhibiting the phosphorylation of JNKs, Aβ precursor protein, and Tau protein. All of these indicated J30-8 as proved isoform-selective JNK3 inhibitors that might serve as a useful tool for further JNK3 studies with AD as well as for the development of JNK3 inhibitors for the potential treatment of neurodegenerative diseases.
- 227Zheng, K.; Iqbal, S.; Hernandez, P.; Park, H.; LoGrasso, P. V.; Feng, Y. Design and synthesis of highly potent and isoform selective JNK3 inhibitors: SAR studies on aminopyrazole derivatives. J. Med. Chem. 2014, 57, 10013– 10030, DOI: 10.1021/jm501256y[ACS Full Text], [CAS], Google Scholar227https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvFWns7fJ&md5=fd826c83f112d7270ef669b74e6ef6f0Design and Synthesis of Highly Potent and Isoform Selective JNK3 Inhibitors: SAR Studies on Aminopyrazole DerivativesZheng, Ke; Iqbal, Sarah; Hernandez, Pamela; Park, HaJeung; LoGrasso, Philip V.; Feng, YangboJournal of Medicinal Chemistry (2014), 57 (23), 10013-10030CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The c-jun N-terminal kinase 3 (JNK3) is expressed primarily in the brain. Numerous reports have shown that inhibition of JNK3 is a promising strategy for treatment of neurodegeneration. The optimization of aminopyrazole-based JNK3 inhibitors with improved potency, isoform selectivity, and pharmacol. properties by structure-activity relationship (SAR) studies utilizing biochem. and cell-based assays, and structure-based drug design is reported. These inhibitors had high selectivity over JNK1 and p38α, minimal cytotoxicity, potent inhibition of 6-OHDA-induced mitochondrial membrane potential dissipation and ROS generation, and good drug metab. and pharmacokinetic (DMPK) properties for iv dosing. 26n was profiled against 464 kinases and was found to be highly selective hitting only seven kinases with >80% inhibition at 10 μM. Moreover, 26n showed good soly., good brain penetration, and good DMPK properties. Finally, the crystal structure of 26k in complex with JNK3 was solved at 1.8 Å to explore the binding mode of aminopyrazole based JNK3 inhibitors.
- 228Estrada, A. A.; Sweeney, Z. K. Chemical biology of Leucine-rich repeat kinase 2 (LRRK2) inhibitors. J. Med. Chem. 2015, 58, 6733– 6746, DOI: 10.1021/acs.jmedchem.5b00261[ACS Full Text], [CAS], Google Scholar228https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXntFGiu7g%253D&md5=37336d97c3c51dcea44df4f7a51837c5Chemical Biology of Leucine-Rich Repeat Kinase 2 (LRRK2) InhibitorsEstrada, Anthony A.; Sweeney, Zachary K.Journal of Medicinal Chemistry (2015), 58 (17), 6733-6746CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)There is an urgent need for the development of Parkinson's disease (PD) treatments that can slow disease progression. The leucine-rich repeat kinase 2 (LRRK2) protein has been genetically and functionally linked to PD, and modulation of LRRK2 enzymic activity has been proposed as a novel therapeutic strategy. In this review, we describe the bioactivity of selected small mols. that have been used to inhibit LRRK2 kinase activity in vitro or in vivo. These compds. are important tools for understanding the cellular biol. of LRRK2 and for evaluating the potential of LRRK2 inhibitors as disease-modifying PD therapies.
- 229Kang, U. B.; Marto, J. A. Leucine-rich repeat kinase 2 and Parkinson’s disease. Proteomics 2017, 17, 1600092, DOI: 10.1002/pmic.201600092
- 230Domingos, S.; Duarte, T.; Saraiva, L.; Guedes, R. C.; Moreira, R. Targeting leucine-rich repeat kinase 2 (LRRK2) for the treatment of Parkinson’s disease. Future Med. Chem. 2019, 11, 1953– 1977, DOI: 10.4155/fmc-2018-0484[Crossref], [PubMed], [CAS], Google Scholar230https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhslGksbvN&md5=3d91a8d284e5f764daff0e33782dfa05Targeting leucine-rich repeat kinase 2 (LRRK2) for the treatment of Parkinson's diseaseDomingos, Sofia; Duarte, Teresa; Saraiva, Lucilia; Guedes, Rita C.; Moreira, RuiFuture Medicinal Chemistry (2019), 11 (15), 1953-1977CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)A review. Leucine-rich repeat kinase 2 (LRRK2) is a serine-threonine kinase involved in multiple cellular processes and signaling pathways. LRRK2 mutations are assocd. with autosomal-inherited Parkinson's disease (PD), and evidence suggests that LRRK2 pathogenic variants generally increase kinase activity. Therefore, inhibition of LRRK2 kinase function is a promising therapeutic strategy for PD treatment. The search for drug-like mols. capable of reducing LRRK2 kinase activity in PD led to the design of selective LRRK2 inhibitors predicted to be within the CNS drug-like space. This review highlights the journey that translates chem. tools for interrogating the role of LRRK2 in PD into promising drug candidates, addressing the challenges in discovering selective and brain-penetrant LRRK2 modulators and exploring the structure-activity relationship of distinct LRRK2 inhibitors.
- 231Taymans, J. M.; Greggio, E. LRRK2 kinase inhibition as a therapeutic strategy for Parkinson’s disease, where do we stand?. Curr. Neuropharmacol 2016, 14, 214– 225, DOI: 10.2174/1570159X13666151030102847[Crossref], [PubMed], [CAS], Google Scholar231https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XktlCgu74%253D&md5=f68fc6814e2add4836aefe53321d1199LRRK2 Kinase Inhibition as a Therapeutic Strategy for Parkinson's Disease, Where Do We Stand?Taymans, Jean-Marc; Greggio, ElisaCurrent Neuropharmacology (2016), 14 (3), 214-225CODEN: CNUEAN; ISSN:1875-6190. (Bentham Science Publishers Ltd.)One of the most promising therapeutic targets for potential disease modifying treatment of Parkinson's disease (PD) is leucine-rich repeat kinase 2 (LRRK2). Specifically, targeting LRRK2's kinase function has generated a lot of interest from both industry and academia. This work has yielded several published studies showing the feasibility of developing potent, selective and brain permeable LRRK2 kinase inhibitors. The availability of these exptl. drugs is contributing to filling in the gaps in our knowledge on the safety and efficacy of LRRK2 kinase inhibition. Recent studies of LRRK2 kinase inhibition in preclin. models point to potential undesired effects in peripheral tissues such as lung and kidney. Also, while strategies are now emerging to measure target engagement of LRRK2 inhibitors, there remains an important need to expand efficacy studies in preclin. models of progressive PD. Future work in the LRRK2 inhibition field must therefore be directed towards developing mols. and treatment regimens which demonstrate efficacy in mammalian models of disease in conditions where safety liabilities are reduced to a min.
- 232Reith, A. D.; Bamborough, P.; Jandu, K.; Andreotti, D.; Mensah, L.; Dossang, P.; Choi, H. G.; Deng, X.; Zhang, J.; Alessi, D. R.; Gray, N. S. GSK2578215A; a potent and highly selective 2-arylmethyloxy-5-substitutent-N-arylbenzamide LRRK2 kinase inhibitor. Bioorg. Med. Chem. Lett. 2012, 22, 5625– 5629, DOI: 10.1016/j.bmcl.2012.06.104[Crossref], [PubMed], [CAS], Google Scholar232https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtFCgsrfO&md5=b2bf7c7cb191cd297b8f586daca58ab1GSK2578215A; A potent and highly selective 2-arylmethyloxy-5-substitutent-N-arylbenzamide LRRK2 kinase inhibitorReith, Alastair D.; Bamborough, Paul; Jandu, Karamjit; Andreotti, Daniele; Mensah, Lucy; Dossang, Pamela; Choi, Hwan Geun; Deng, Xianming; Zhang, Jinwei; Alessi, Dario R.; Gray, Nathanael S.Bioorganic & Medicinal Chemistry Letters (2012), 22 (17), 5625-5629CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for some forms of Parkinson's disease. Here we report the discovery and characterization of 2-arylmethyloxy-5-subtitutent-N-arylbenzamides with potent LRRK2 activities exemplified by GSK2578215A which exhibits biochem. IC50s of around 10 nM against both wild-type LRRK2 and the G2019S mutant. GSK2578215A exhibits exceptionally high selectivity for LRRK2 across the kinome, substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concn. of 0.3-1.0 μM in cells and in mouse spleen and kidney, but not in brain, following i.p. injection of 100 mg/kg.
- 233Estrada, A. A.; Liu, X.; Baker-Glenn, C.; Beresford, A.; Burdick, D. J.; Chambers, M.; Chan, B. K.; Chen, H.; Ding, X.; DiPasquale, A. G.; Dominguez, S. L.; Dotson, J.; Drummond, J.; Flagella, M.; Flynn, S.; Fuji, R.; Gill, A.; Gunzner-Toste, J.; Harris, S. F.; Heffron, T. P.; Kleinheinz, T.; Lee, D. W.; Le Pichon, C. E.; Lyssikatos, J. P.; Medhurst, A. D.; Moffat, J. G.; Mukund, S.; Nash, K.; Scearce-Levie, K.; Sheng, Z.; Shore, D. G.; Tran, T.; Trivedi, N.; Wang, S.; Zhang, S.; Zhang, X.; Zhao, G.; Zhu, H.; Sweeney, Z. K. Discovery of highly potent, selective, and brain-penetrable leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitors. J. Med. Chem. 2012, 55, 9416– 9433, DOI: 10.1021/jm301020q[ACS Full Text], [CAS], Google Scholar233https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlGktbfO&md5=9fc7ccca9c973a960e7393c79c1255faDiscovery of Highly Potent, Selective, and Brain-Penetrable Leucine-Rich Repeat Kinase 2 (LRRK2) Small Molecule InhibitorsEstrada, Anthony A.; Liu, Xingrong; Baker-Glenn, Charles; Beresford, Alan; Burdick, Daniel J.; Chambers, Mark; Chan, Bryan K.; Chen, Huifen; Ding, Xiao; DiPasquale, Antonio G.; Dominguez, Sara L.; Dotson, Jennafer; Drummond, Jason; Flagella, Michael; Flynn, Sean; Fuji, Reina; Gill, Andrew; Gunzner-Toste, Janet; Harris, Seth F.; Heffron, Timothy P.; Kleinheinz, Tracy; Lee, Donna W.; Le Pichon, Claire E.; Lyssikatos, Joseph P.; Medhurst, Andrew D.; Moffat, John G.; Mukund, Susmith; Nash, Kevin; Scearce-Levie, Kimberly; Sheng, Zejuan; Shore, Daniel G.; Tran, Thuy; Trivedi, Naimisha; Wang, Shumei; Zhang, Shuo; Zhang, Xiaolin; Zhao, Guiling; Zhu, Haitao; Sweeney, Zachary K.Journal of Medicinal Chemistry (2012), 55 (22), 9416-9433CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)There is a high demand for potent, selective, and brain-penetrant small mol. inhibitors of leucine-rich repeat kinase 2 (LRRK2) to test whether inhibition of LRRK2 kinase activity is a potentially viable treatment option for Parkinson's disease patients. Herein we disclose the use of property and structure-based drug design for the optimization of highly ligand efficient aminopyrimidine lead compds. High throughput in vivo rodent cassette pharmacokinetic studies enabled rapid validation of in vitro-in vivo correlations. Guided by this data, optimal design parameters were established. Effective incorporation of these guidelines into our mol. design process resulted in the discovery of small mol. inhibitors such as GNE-7915 (18, I) and 19, which possess an ideal balance of LRRK2 cellular potency, broad kinase selectivity, metabolic stability, and brain penetration across multiple species. Advancement of GNE-7915 into rodent and higher species toxicity studies enabled risk assessment for early development.
- 234Henderson, J. L.; Kormos, B. L.; Hayward, M. M.; Coffman, K. J.; Jasti, J.; Kurumbail, R. G.; Wager, T. T.; Verhoest, P. R.; Noell, G. S.; Chen, Y.; Needle, E.; Berger, Z.; Steyn, S. J.; Houle, C.; Hirst, W. D.; Galatsis, P. Discovery and preclinical profiling of 3-[4-(morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475), a highly potent, selective, brain penetrant, and in vivo active LRRK2 kinase inhibitor. J. Med. Chem. 2015, 58, 419– 432, DOI: 10.1021/jm5014055[ACS Full Text], [CAS], Google Scholar234https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVens7%252FO&md5=d970c348ae4ec899b504e28060b21f13Discovery and Preclinical Profiling of 3-[4-(Morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475), a Highly Potent, Selective, Brain Penetrant, and in Vivo Active LRRK2 Kinase InhibitorHenderson, Jaclyn L.; Kormos, Bethany L.; Hayward, Matthew M.; Coffman, Karen J.; Jasti, Jayasankar; Kurumbail, Ravi G.; Wager, Travis T.; Verhoest, Patrick R.; Noell, G. Stephen; Chen, Yi; Needle, Elie; Berger, Zdenek; Steyn, Stefanus J.; Houle, Christopher; Hirst, Warren D.; Galatsis, PaulJournal of Medicinal Chemistry (2015), 58 (1), 419-432CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson's disease (PD) by genome-wide assocn. studies (GWAS). The most common LRRK2 mutation, G2019S, which is relatively rare in the total population, gives rise to increased kinase activity. As such, LRRK2 kinase inhibitors are potentially useful in the treatment of PD. We herein disclose the discovery and optimization of a novel series of potent LRRK2 inhibitors, focusing on improving kinome selectivity using a surrogate crystallog. approach. This resulted in the identification of 14 (PF-06447475), a highly potent, brain penetrant and selective LRRK2 inhibitor which has been further profiled in in vivo safety and pharmacodynamic studies.
- 235Williamson, D. S.; Smith, G. P.; Acheson-Dossang, P.; Bedford, S. T.; Chell, V.; Chen, I. J.; Daechsel, J. C. A.; Daniels, Z.; David, L.; Dokurno, P.; Hentzer, M.; Herzig, M. C.; Hubbard, R. E.; Moore, J. D.; Murray, J. B.; Newland, S.; Ray, S. C.; Shaw, T.; Surgenor, A. E.; Terry, L.; Thirstrup, K.; Wang, Y. K.; Christensen, K. V. Design of Leucine-rich repeat kinase 2 (LRRK2) inhibitors using a crystallographic surrogate derived from Checkpoint kinase 1 (CHK1). J. Med. Chem. 2017, 60, 8945– 8962, DOI: 10.1021/acs.jmedchem.7b01186[ACS Full Text], [CAS], Google Scholar235https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1Gms77I&md5=c77bfc36dbd0048d462eaac1531bdc16Design of leucine-rich repeat kinase 2 (LRRK2) inhibitors using a crystallographic surrogate derived from checkpoint kinase 1 (CHK1)Williamson, Douglas S.; Smith, Garrick P.; Acheson-Dossang, Pamela; Bedford, Simon T.; Chell, Victoria; Chen, I-Jen; Daechsel, Justus C. A.; Daniels, Zoe; David, Laurent; Dokurno, Pawel; Hentzer, Morten; Herzig, Martin C.; Hubbard, Roderick E.; Moore, Jonathan D.; Murray, James B.; Newland, Samantha; Ray, Stuart C.; Shaw, Terry; Surgenor, Allan E.; Terry, Lindsey; Thirstrup, Kenneth; Wang, Yikang; Christensen, Kenneth V.Journal of Medicinal Chemistry (2017), 60 (21), 8945-8962CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Mutations in leucine-rich repeat kinase 2 (LRRK2), such as G2019S, are assocd. with an increased risk of developing Parkinson's disease. Surrogates for the LRRK2 kinase domain based on checkpoint kinase 1 (CHK1) mutants were designed, expressed in insect cells infected with baculovirus, purified, and crystd. X-ray structures of the surrogates complexed with known LRRK2 inhibitors rationalized compd. potency and selectivity. The CHK1 10-point mutant was preferred, following assessment of surrogate binding affinity with LRRK2 inhibitors. Fragment hit-derived arylpyrrolo[2,3-b]pyridine LRRK2 inhibitors underwent structure-guided optimization using this crystallog. surrogate. LRRK2-pSer935 HEK293 IC50 data for 22 were consistent with binding to Ala2016 in LRRK2 (equiv. to Ala147 in CHK1 10-point mutant structure). Compd. 22 was shown to be potent, moderately selective, orally available, and brain-penetrant in wild-type mice, and confirmation of target engagement was demonstrated, with LRRK2-pSer935 IC50 values for 22 in mouse brain and kidney being 1.3 and 5 nM, resp.
- 236Scott, J. D.; DeMong, D. E.; Greshock, T. J.; Basu, K.; Dai, X.; Harris, J.; Hruza, A.; Li, S. W.; Lin, S. I.; Liu, H.; Macala, M. K.; Hu, Z.; Mei, H.; Zhang, H.; Walsh, P.; Poirier, M.; Shi, Z. C.; Xiao, L.; Agnihotri, G.; Baptista, M. A.; Columbus, J.; Fell, M. J.; Hyde, L. A.; Kuvelkar, R.; Lin, Y.; Mirescu, C.; Morrow, J. A.; Yin, Z.; Zhang, X.; Zhou, X.; Chang, R. K.; Embrey, M. W.; Sanders, J. M.; Tiscia, H. E.; Drolet, R. E.; Kern, J. T.; Sur, S. M.; Renger, J. J.; Bilodeau, M. T.; Kennedy, M. E.; Parker, E. M.; Stamford, A. W.; Nargund, R.; McCauley, J. A.; Miller, M. W. Discovery of a 3-(4-pyrimidinyl) indazole (MLi-2), an orally available and selective Leucine-rich repeat kinase 2 (LRRK2) inhibitor that reduces brain kinase activity. J. Med. Chem. 2017, 60, 2983– 2992, DOI: 10.1021/acs.jmedchem.7b00045[ACS Full Text], [CAS], Google Scholar236https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjsFaltL8%253D&md5=4d18d0d3288d0a9330c385776a9f0b7cDiscovery of a 3-(4-Pyrimidinyl) Indazole (MLi-2), an Orally Available and Selective Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitor that Reduces Brain Kinase ActivityScott, Jack D.; DeMong, Duane E.; Greshock, Thomas J.; Basu, Kallol; Dai, Xing; Harris, Joel; Hruza, Alan; Li, Sarah W.; Lin, Sue-Ing; Liu, Hong; Macala, Megan K.; Hu, Zhiyong; Mei, Hong; Zhang, Honglu; Walsh, Paul; Poirier, Marc; Shi, Zhi-Cai; Xiao, Li; Agnihotri, Gautam; Baptista, Marco A. S.; Columbus, John; Fell, Matthew J.; Hyde, Lynn A.; Kuvelkar, Reshma; Lin, Yinghui; Mirescu, Christian; Morrow, John A.; Yin, Zhizhang; Zhang, Xiaoping; Zhou, Xiaoping; Chang, Ronald K.; Embrey, Mark W.; Sanders, John M.; Tiscia, Heather E.; Drolet, Robert E.; Kern, Jonathan T.; Sur, Sylvie M.; Renger, John J.; Bilodeau, Mark T.; Kennedy, Matthew E.; Parker, Eric M.; Stamford, Andrew W.; Nargund, Ravi; McCauley, John A.; Miller, Michael W.Journal of Medicinal Chemistry (2017), 60 (7), 2983-2992CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Leucine-Rich Repeat Kinase 2 (LRRK2) is a large, multidomain protein which contains a kinase domain and GTPase domain among other regions. Individuals possessing gain of function mutations in the kinase domain such as the most prevalent G2019S mutation have been assocd. with an increased risk for the development of Parkinson's Disease (PD). Given this genetic validation for inhibition of LRRK2 kinase activity as a potential means of effecting disease progression, the team set out to develop LRRK2 inhibitors to test this hypothesis. A high throughput screen of the compd. collection afforded a no. of promising indazole leads which were truncated in order to identify a min. pharmacophore. Further optimization of these indazoles led to the development of MLi-2 I: a potent, highly selective, orally available, brain penetrant inhibitor of LRRK2.
- 237Fuji, R. N.; Flagella, M.; Baca, M.; Baptista, M. A. S.; Brodbeck, J.; Chan, B. K.; Fiske, B. K.; Honigberg, L.; Jubb, A. M.; Katavolos, P.; Lee, D. W.; Lewin-Koh, S. C.; Lin, T.; Liu, X.; Liu, S.; Lyssikatos, J. P.; O’Mahony, J.; Reichelt, M.; Roose-Girma, M.; Sheng, Z.; Sherer, T.; Smith, A.; Solon, M.; Sweeney, Z. K.; Tarrant, J.; Urkowitz, A.; Warming, S.; Yaylaoglu, M.; Zhang, S.; Zhu, H.; Estrada, A. A.; Watts, R. J. Effect of selective LRRK2 kinase inhibition on nonhuman primate lung. Sci. Transl. Med. 2015, 7, 273ra15, DOI: 10.1126/scitranslmed.aaa3634
- 238Qin, Q.; Zhi, L. T.; Li, X. T.; Yue, Z. Y.; Li, G. Z.; Zhang, H. Effects of LRRK2 inhibitors on nigrostriatal dopaminergic neurotransmission. CNS Neurosci. Ther. 2017, 23, 162– 173, DOI: 10.1111/cns.12660[Crossref], [PubMed], [CAS], Google Scholar238https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1WitL0%253D&md5=cab0675b70721325cfcaf3b63178a079Effects of LRRK2 Inhibitors on Nigrostriatal Dopaminergic NeurotransmissionQin, Qi; Zhi, Lian-Teng; Li, Xian-Ting; Yue, Zhen-Yu; Li, Guo-Zhong; Zhang, HuiCNS Neuroscience & Therapeutics (2017), 23 (2), 162-173CODEN: CNTNAB; ISSN:1755-5930. (Wiley-Blackwell)Introduction : Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most prevalent cause of familial and sporadic Parkinson's disease (PD). Because most pathogenic LRRK2 mutations result in enhanced kinase activity, it suggests that LRRK2 inhibitors may serve as a potential treatment for PD. To evaluate whether LRRK2 inhibitors are effective therapies for PD, it is crucial to know whether LRRK2 inhibitors will affect dopaminergic (DAergic) neurotransmission. However, to date, there is no study to investigate the impact of LRRK2 inhibitors on DAergic neurotransmission. Aims : To address this gap in knowledge, we examd. the effects of three types of LRRK2 inhibitors (LRRK2-IN-1, GSK2578215A, and GNE-7915) on dopamine (DA) release in the dorsal striatum using fast-scan cyclic voltammetry and DA neuron firing in the substantia nigra pars compacta (SNpc) using patch clamp in mouse brain slices. Results : We found that LRRK2-IN-1 at a concn. higher than 1 μM causes off-target effects and decreases DA release, whereas GSK2578215A and GNE-7915 do not. All three inhibitors at 1 μM have no effect on DA release and DA neuron firing rate. We have further assessed the effects of the inhibitors in two preclin. LRRK2 mouse models (i.e., BAC transgenic hG2019S and hR1441G) and demonstrated that GNE-7915 enhances DA release and synaptic vesicle mobilization/recycling. Conclusion : GNE-7915 can be validated for further therapeutic development for PD.
- 239Ishimoto, T.; Lanaspa, M. A.; Rivard, C. J.; Roncal-Jimenez, C. A.; Orlicky, D. J.; Cicerchi, C.; McMahan, R. H.; Abdelmalek, M. F.; Rosen, H. R.; Jackman, M. R.; MacLean, P. S.; Diggle, C. P.; Asipu, A.; Inaba, S.; Kosugi, T.; Sato, W.; Maruyama, S.; Sanchez-Lozada, L. G.; Sautin, Y. Y.; Hill, J. O.; Bonthron, D. T.; Johnson, R. J. High-fat and high-sucrose (western) diet induces steatohepatitis that is dependent on fructokinase. Hepatology 2013, 58, 1632– 1643, DOI: 10.1002/hep.26594[Crossref], [PubMed], [CAS], Google Scholar239https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslWqsLvE&md5=d4544aba25dd28f735c4e0b76e02cc48High-fat and high-sucrose (western) diet induces steatohepatitis that is dependent on fructokinaseIshimoto, Takuji; Lanaspa, Miguel A.; Rivard, Christopher J.; Roncal-Jimenez, Carlos A.; Orlicky, David J.; Cicerchi, Christina; McMahan, Rachel H.; Abdelmalek, Manal F.; Rosen, Hugo R.; Jackman, Matthew R.; MacLean, Paul S.; Diggle, Christine P.; Asipu, Aruna; Inaba, Shinichiro; Kosugi, Tomoki; Sato, Waichi; Maruyama, Shoichi; Sanchez-Lozada, Laura G.; Sautin, Yuri Y.; Hill, James O.; Bonthron, David T.; Johnson, Richard J.Hepatology (Hoboken, NJ, United States) (2013), 58 (5), 1632-1643CODEN: HPTLD9; ISSN:0270-9139. (John Wiley & Sons, Inc.)Fructose intake from added sugars has been implicated as a cause of nonalcoholic fatty liver disease. Here we tested the hypothesis that fructose may interact with a high-fat diet to induce fatty liver, and to det. if this was dependent on a key enzyme in fructose metab., fructokinase. Wild-type or fructokinase knockout mice were fed a low-fat (11%), high-fat (36%), or high-fat (36%) and high-sucrose (30%) diet for 15 wk. Both wild-type and fructokinase knockout mice developed obesity with mild hepatic steatosis and no evidence of hepatic inflammation on a high-fat diet compared to a low-fat diet. In contrast, wild-type mice fed a high-fat and high-sucrose diet developed more severe hepatic steatosis with low-grade inflammation and fibrosis, as noted by increased CD68, tumor necrosis factor alpha, monocyte chemoattractant protein-1, alpha-smooth muscle actin, and collagen I and TIMP1 expression. These changes were prevented in the fructokinase knockout mice. Conclusion: An additive effect of high-fat and high-sucrose diet on the development of hepatic steatosis exists. Further, the combination of sucrose with high-fat diet may induce steatohepatitis. The protection in fructokinase knockout mice suggests a key role for fructose (from sucrose) in this development of steatohepatitis. These studies emphasize the important role of fructose in the development of fatty liver and nonalcoholic steatohepatitis. (Hepatol. 2013;58:1632-1643).
- 240Gibbs, A. C.; Abad, M. C.; Zhang, X.; Tounge, B. A.; Lewandowski, F. A.; Struble, G. T.; Sun, W.; Sui, Z.; Kuo, L. C. Electron density guided fragment-based lead discovery of ketohexokinase inhibitors. J. Med. Chem. 2010, 53, 7979– 7991, DOI: 10.1021/jm100677s[ACS Full Text], [CAS], Google Scholar240https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtlGntr%252FF&md5=3abdf4ac63d4afcf6a4db484d0d87259Electron Density Guided Fragment-Based Lead Discovery of Ketohexokinase InhibitorsGibbs, Alan C.; Abad, Marta C.; Zhang, Xuqing; Tounge, Brett A.; Lewandowski, Francis A.; Struble, Geoffrey T.; Sun, Weimei; Sui, Zhihua; Kuo, Lawrence C.Journal of Medicinal Chemistry (2010), 53 (22), 7979-7991CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A fragment-based drug design paradigm has been successfully applied in the discovery of lead series of ketohexokinase inhibitors. The paradigm consists of three iterations of design, synthesis, and x-ray crystallog. screening to progress low mol. wt. fragments to leadlike compds. Applying electron d. of fragments within the protein binding site as defined by x-ray crystallog., one can generate target specific leads without the use of affinity data. Our approach contrasts with most fragment-based drug design methodol. where soln. activity is a main design guide. Herein we describe the discovery of submicromolar ketohexokinase inhibitors with promising druglike properties.
- 241Huard, K.; Ahn, K.; Amor, P.; Beebe, D. A.; Borzilleri, K. A.; Chrunyk, B. A.; Coffey, S. B.; Cong, Y.; Conn, E. L.; Culp, J. S.; Dowling, M. S.; Gorgoglione, M. F.; Gutierrez, J. A.; Knafels, J. D.; Lachapelle, E. A.; Pandit, J.; Parris, K. D.; Perez, S.; Pfefferkorn, J. A.; Price, D. A.; Raymer, B.; Ross, T. T.; Shavnya, A.; Smith, A. C.; Subashi, T. A.; Tesz, G. J.; Thuma, B. A.; Tu, M.; Weaver, J. D.; Weng, Y.; Withka, J. M.; Xing, G.; Magee, T. V. Discovery of fragment-derived small molecules for in vivo inhibition of Ketohexokinase (KHK). J. Med. Chem. 2017, 60, 7835– 7849, DOI: 10.1021/acs.jmedchem.7b00947[ACS Full Text], [CAS], Google Scholar241https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsVagu7jK&md5=d83bc39986e54a0f41e8f310b725ab92Discovery of Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK)Huard, Kim; Ahn, Kay; Amor, Paul; Beebe, David A.; Borzilleri, Kris A.; Chrunyk, Boris A.; Coffey, Steven B.; Cong, Yang; Conn, Edward L.; Culp, Jeffrey S.; Dowling, Matthew S.; Gorgoglione, Matthew F.; Gutierrez, Jemy A.; Knafels, John D.; Lachapelle, Erik A.; Pandit, Jayvardhan; Parris, Kevin D.; Perez, Sylvie; Pfefferkorn, Jeffrey A.; Price, David A.; Raymer, Brian; Ross, Trenton T.; Shavnya, Andre; Smith, Aaron C.; Subashi, Timothy A.; Tesz, Gregory J.; Thuma, Benjamin A.; Tu, Meihua; Weaver, John D.; Weng, Yan; Withka, Jane M.; Xing, Gang; Magee, Thomas V.Journal of Medicinal Chemistry (2017), 60 (18), 7835-7849CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Increased fructose consumption and its subsequent metab. have been implicated in hepatic steatosis, dyslipidemia, obesity, and insulin resistance in humans. Since ketohexokinase (KHK) is the principal enzyme responsible for fructose metab., identification of a selective KHK inhibitor may help to further elucidate the effect of KHK inhibition on these metabolic disorders. Until now, studies on KHK inhibition with small mols. have been limited due to the lack of viable in vivo pharmacol. tools. Herein the authors report the discovery of 12 (6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-2-((S)-3-hydroxy-3-methylpyrrolidin-1-yl)-4-(trifluoromethyl)nicotinonitrile), a selective KHK inhibitor with potency and properties suitable for evaluating KHK inhibition in rat models. Key structural features interacting with KHK were discovered through fragment-based screening and subsequent optimization using structure-based drug design, and parallel medicinal chem. led to the identification of pyridine 12.
- 242Cannavo, A.; Komici, K.; Bencivenga, L.; D’Amico, M. L.; Gambino, G.; Liccardo, D.; Ferrara, N.; Rengo, G. GRK2 as a therapeutic target for heart failure. Expert Opin. Ther. Targets 2018, 22, 75– 83, DOI: 10.1080/14728222.2018.1406925[Crossref], [PubMed], [CAS], Google Scholar242https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFahtrrM&md5=0727276deb7a0409c71f5bfcf3bcf007GRK2 as a therapeutic target for heart failureCannavo, Alessandro; Komici, Klara; Bencivenga, Leonardo; D'amico, Maria Loreta; Gambino, Giuseppina; Liccardo, Daniela; Ferrara, Nicola; Rengo, GiuseppeExpert Opinion on Therapeutic Targets (2018), 22 (1), 75-83CODEN: EOTTAO; ISSN:1472-8222. (Taylor & Francis Ltd.)A review. G protein-coupled receptor (GPCR) kinase-2 (GRK2) is a regulator of GPCRs, in particular β-adrenergic receptors (ARs), and as demonstrated by decades of investigation, it has a pivotal role in the development and progression of cardiovascular disease, like heart failure (HF). Indeed elevated levels and activity of this kinase are able to promote the dysfunction of both cardiac and adrenal α- and β-ARs and to dysregulate other protective signaling pathway, such as sphingosine 1-phospate and insulin. Moreover, recent discoveries suggest that GRK2 can signal independently from GPCRs, in a 'non-canonical' manner, via interaction with non-GPCR mol. or via its mitochondrial localization. Based on this premise, GRK2 inhibition or its genetic deletion has been tested in several disparate animal models of cardiovascular disease, showing to protect the heart from adverse remodeling and dysfunction. HF is one of the leading cause of death worldwide with enormous health care costs. For this reason, the identification of new therapeutic targets like GRK2 and strategies such as its inhibition represents a new hope in the fight against HF development and progression. Herein, we will update the readers about the 'state-of-art' of GRK2 inhibition as a potent therapeutic strategy in HF.
- 243Eschenhagen, T. β-adrenergic signaling in heart failure-adapt or die. Nat. Med. 2008, 14, 485– 487, DOI: 10.1038/nm0508-485[Crossref], [PubMed], [CAS], Google Scholar243https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXlsFCnu78%253D&md5=116860d5dfec89324c623a51bfe99f89β-adrenergic signaling in heart failure-adapt or dieEschenhagen, ThomasNature Medicine (New York, NY, United States) (2008), 14 (5), 485-487CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)A review. About 25% of the African-American population carries a gene variant that seems to protect against heart failure. The findings may have implications for the use of β-blockers (pages 510-517).
- 244Rockman, H. A.; Chien, K. R.; Choi, D. J.; Iaccarino, G.; Hunter, J. J.; Ross, J., Jr; Lefkowitz, R. J.; Koch, W. J. Expression of a β-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice. Proc. Natl. Acad. Sci. U. S. A. 1998, 95, 7000– 7005, DOI: 10.1073/pnas.95.12.7000[Crossref], [PubMed], [CAS], Google Scholar244https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXjslyms7Y%253D&md5=a456743770d269ba225b206c7657fb6aExpression of a β-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted miceRockman, Howard A.; Chien, Kenneth R.; Choi, Dong-Ju; Iaccarino, Guido; Hunter, John J.; Ross, John, Jr.; Lefkowitz, Robert J.; Koch, Walter J.Proceedings of the National Academy of Sciences of the United States of America (1998), 95 (12), 7000-7005CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Heart failure is accompanied by severely impaired β-adrenergic receptor (βAR) function, which includes loss of βAR d. and functional uncoupling of remaining receptors. An important mechanism for the rapid desensitization of βAR function is agonist-stimulated receptor phosphorylation by the βAR kinase (βARK1), an enzyme known to be elevated in failing human heart tissue. To investigate whether alterations in βAR function contribute to the development of myocardial failure, transgenic mice with cardiac-restricted overexpression of either a peptide inhibitor of βARK1 or the β2AR were mated into a genetic model of murine heart failure (MLP-/-). In vivo cardiac function was assessed by echocardiog. and cardiac catheterization. Both MLP-/- and MLP-/-/β2AR mice had enlarged left ventricular (LV) chambers with significantly reduced fractional shortening and mean velocity of circumferential fiber shortening. In contrast, MLP-/-/βARKct mice had normal LV chamber size and function. Basal LV contractility in the MLP-/-/βARKct mice, as measured by LV dP/dtmax, was increased significantly compared with the MLP-/- mice but less than controls. Importantly, heightened βAR desensitization in the MLP-/- mice, measured in vivo (responsiveness to isoproterenol) and in vitro (isoproterenol-stimulated membrane adenylyl cyclase activity), was completely reversed with overexpression of the βARK1 inhibitor. The authors report here the striking finding that overexpression of this inhibitor prevents the development of cardiomyopathy in this murine model of heart failure. These findings implicate abnormal βAR-G protein coupling in the pathogenesis of the failing heart and point the way toward development of agents to inhibit βARK1 as a novel mode of therapy.
- 245Raake, P. W.; Vinge, L. E.; Gao, E.; Boucher, M.; Rengo, G.; Chen, X.; DeGeorge, B. R., Jr; Matkovich, S.; Houser, S. R.; Most, P.; Eckhart, A. D.; Dorn, G. W., 2nd; Koch, W. J. G protein-coupled receptor kinase 2 ablation in cardiac myocytes before or after myocardial infarction prevents heart failure. Circ. Res. 2008, 103, 413– 422, DOI: 10.1161/CIRCRESAHA.107.168336[Crossref], [PubMed], [CAS], Google Scholar245https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXptlKnurc%253D&md5=2ee73b14bd9dd3db3ec387e5a70ed211G Protein-Coupled Receptor Kinase 2 Ablation in Cardiac Myocytes Before or After Myocardial Infarction Prevents Heart FailureRaake, Philip W.; Vinge, Leif E.; Gao, Erhe; Boucher, Matthieu; Rengo, Giuseppe; Chen, Xiongwen; DeGeorge, Brent R., Jr.; Matkovich, Scot; Houser, Steven R.; Most, Patrick; Eckhart, Andrea D.; Dorn, Gerald W., II; Koch, Walter J.Circulation Research (2008), 103 (4), 413-422CODEN: CIRUAL; ISSN:0009-7330. (Lippincott Williams & Wilkins)Myocardial G protein-coupled receptor kinase (GRK)2 is a crit. regulator of cardiac β-adrenergic receptor (βAR) signaling and cardiac function. Its upregulation in heart failure may further depress cardiac function and contribute to mortality in this syndrome. Preventing GRK2 translocation to activated βAR with a GRK2-derived peptide that binds Gβγ (βARKct) has benefited some models of heart failure, but the precise mechanism is uncertain, because GRK2 is still present and βARKct has other potential effects. We generated mice in which cardiac myocyte GRK2 expression was normal during embryonic development but was ablated after birth (αMHC-Cre×GRK2 fl/fl) or only after administration of tamoxifen (αMHC-MerCreMer×GRK2 fl/fl) and examd. the consequences of GRK2 ablation before and after surgical coronary artery ligation on cardiac adaptation after myocardial infarction. Absence of GRK2 before coronary artery ligation prevented maladaptive postinfarction remodeling and preserved βAR responsiveness. Strikingly, GRK2 ablation initiated 10 days after infarction increased survival, enhanced cardiac contractile performance, and halted ventricular remodeling. These results demonstrate a specific causal role for GRK2 in postinfarction cardiac remodeling and heart failure and support therapeutic approaches of targeting GRK2 or restoring βAR signaling by other means to improve outcomes in heart failure.
- 246Thal, D. M.; Homan, K. T.; Chen, J.; Wu, E. K.; Hinkle, P. M.; Huang, Z. M.; Chuprun, J. K.; Song, J.; Gao, E.; Cheung, J. Y.; Sklar, L. A.; Koch, W. J.; Tesmer, J. J. Paroxetine is a direct inhibitor of g protein-coupled receptor kinase 2 and increases myocardial contractility. ACS Chem. Biol. 2012, 7, 1830– 1839, DOI: 10.1021/cb3003013[ACS Full Text], [CAS], Google Scholar246https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtFOntLfI&md5=08df20fa41a8b3241640db5de557a001Paroxetine Is a Direct Inhibitor of G Protein-Coupled Receptor Kinase 2 and Increases Myocardial ContractilityThal, David M.; Homan, Kristoff T.; Chen, Jun; Wu, Emily K.; Hinkle, Patricia M.; Huang, Z. Maggie; Chuprun, J. Kurt; Song, Jianliang; Gao, Erhe; Cheung, Joseph Y.; Sklar, Larry A.; Koch, Walter J.; Tesmer, John J. G.ACS Chemical Biology (2012), 7 (11), 1830-1839CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)G protein-coupled receptor kinase 2 (GRK2) is a well-established therapeutic target for the treatment of heart failure. Herein we identify the selective serotonin reuptake inhibitor (SSRI) paroxetine as a selective inhibitor of GRK2 activity both in vitro and in living cells. In the crystal structure of the GRK2·paroxetine-Gβγ complex, paroxetine binds in the active site of GRK2 and stabilizes the kinase domain in a novel conformation in which a unique regulatory loop forms part of the ligand binding site. Isolated cardiomyocytes show increased isoproterenol-induced shortening and contraction amplitude in the presence of paroxetine, and pretreatment of mice with paroxetine before isoproterenol significantly increases left ventricular inotropic reserve in vivo with no significant effect on heart rate. Neither is obsd. in the presence of the SSRI fluoxetine. Our structural and functional results validate a widely available drug as a selective chem. probe for GRK2 and represent a starting point for the rational design of more potent and specific GRK2 inhibitors.
- 247Schumacher, S. M.; Gao, E.; Zhu, W.; Chen, X.; Chuprun, J. K.; Feldman, A. M.; Tesmer, J. J. G.; Koch, W. J. Paroxetine-mediated GRK2 inhibition reverses cardiac dysfunction and remodeling after myocardial infarction. Sci. Transl. Med. 2015, 7, 277ra31, DOI: 10.1126/scitranslmed.aaa0154
- 248Guccione, M.; Ettari, R.; Taliani, S.; Da Settimo, F.; Zappala, M.; Grasso, S. G-protein-coupled receptor kinase 2 (GRK2) inhibitors: current trends and future perspectives. J. Med. Chem. 2016, 59, 9277– 9294, DOI: 10.1021/acs.jmedchem.5b01939[ACS Full Text], [CAS], Google Scholar248https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtV2gsL3L&md5=76c06627842335aae6430144d5f03e7aG-Protein-Coupled Receptor Kinase 2 (GRK2) Inhibitors: Current Trends and Future PerspectivesGuccione, Manuela; Ettari, Roberta; Taliani, Sabrina; Da Settimo, Federico; Zappala, Maria; Grasso, SilvanaJournal of Medicinal Chemistry (2016), 59 (20), 9277-9294CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. G-protein-coupled receptor kinase 2 (GRK2) is a G-protein-coupled receptor kinase that is ubiquitously expressed in many tissues and regulates various intracellular mechanisms. The up- or down-regulation of GRK2 correlates with several pathol. disorders. GRK2 plays an important role in the maintenance of heart structure and function; thus, this kinase is involved in many cardiovascular diseases. GRK2 up-regulation can worsen cardiac ischemia; furthermore, increased kinase levels occur during the early stages of heart failure and in hypertensive subjects. GRK2 up-regulation can lead to changes in the insulin signaling cascade, which can translate to insulin resistance. Increased GRK2 levels also correlate with the degree of cognitive impairment that is typically obsd. in Alzheimer's disease. This article reviews the most potent and selective GRK2 inhibitors that have been developed. The authors focus on their mechanism of action, inhibition profile, and structure-activity relationships to provide insight into the further development of GRK2 inhibitors as drug candidates.
- 249Thal, D. M.; Yeow, R. Y.; Schoenau, C.; Huber, J.; Tesmer, J. J. Molecular mechanism of selectivity among G protein-coupled receptor kinase 2 inhibitors. Mol. Pharmacol. 2011, 80, 294– 303, DOI: 10.1124/mol.111.071522[Crossref], [PubMed], [CAS], Google Scholar249https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXps1yqsL0%253D&md5=cde68787c0f4f20131ffe88ddbfd9284Molecular mechanism of selectivity among G protein-coupled receptor kinase 2 inhibitorsThal, David M.; Yeow, Raymond Y.; Schoenau, Christian; Huber, Jochen; Tesmer, John J. G.Molecular Pharmacology (2011), 80 (2), 294-303CODEN: MOPMA3; ISSN:0026-895X. (American Society for Pharmacology and Experimental Therapeutics)G protein-coupled receptors (GPCRs) are key regulators of cell physiol. and control processes ranging from glucose homeostasis to contractility of the heart. A major mechanism for the desensitization of activated GPCRs is their phosphorylation by GPCR kinases (GRKs). Overexpression of GRK2 is strongly linked to heart failure, and GRK2 has long been considered a pharmaceutical target for the treatment of cardiovascular disease. Several lead compds. developed by Takeda Pharmaceuticals show high selectivity for GRK2 and therapeutic potential for the treatment of heart failure. To understand how these drugs achieve their selectivity, we detd. crystal structures of the bovine GRK2-Gβγ complex in the presence of two of these inhibitors. Comparison with the apoGRK2-Gβγ structure demonstrates that the compds. bind in the kinase active site in a manner similar to that of the AGC kinase inhibitor balanol. Both balanol and the Takeda compds. induce a slight closure of the kinase domain, the degree of which correlates with the potencies of the inhibitors. Based on our crystal structures and homol. modeling, we identified five amino acids surrounding the inhibitor binding site that we hypothesized could contribute to inhibitor selectivity. However, our results indicate that these residues are not major determinants of selectivity among GRK subfamilies. Rather, selectivity is achieved by the stabilization of a unique inactive conformation of the GRK2 kinase domain.
- 250Waldschmidt, H. V.; Homan, K. T.; Cruz-Rodriguez, O.; Cato, M. C.; Waninger-Saroni, J.; Larimore, K. M.; Cannavo, A.; Song, J.; Cheung, J. Y.; Kirchhoff, P. D.; Koch, W. J.; Tesmer, J. J.; Larsen, S. D. Structure-based design, synthesis, and biological evaluation of highly selective and potent G protein-coupled receptor kinase 2 inhibitors. J. Med. Chem. 2016, 59, 3793– 3807, DOI: 10.1021/acs.jmedchem.5b02000[ACS Full Text], [CAS], Google Scholar250https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XlsVOgtL8%253D&md5=149b7722909617a88d439ae3d90338a4Structure-Based Design, Synthesis, and Biological Evaluation of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 InhibitorsWaldschmidt, Helen V.; Homan, Kristoff T.; Cruz-Rodriguez, Osvaldo; Cato, Marilyn C.; Waninger-Saroni, Jessica; Larimore, Kelly L.; Cannavo, Alessandro; Song, Jianliang; Cheung, Joseph Y.; Kirchhoff, Paul D.; Koch, Walter J.; Tesmer, John J. G.; Larsen, Scott D.Journal of Medicinal Chemistry (2016), 59 (8), 3793-3807CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)G protein-coupled receptors (GPCRs) are central to many physiol. processes. Regulation of this superfamily of receptors is controlled by GPCR kinases (GRKs), some of which have been implicated in heart failure. GSK180736A, developed as a Rho-assocd. coiled-coil kinase 1 (ROCK1) inhibitor, was identified as an inhibitor of GRK2 and co-crystd. in the active site. Guided by its binding pose overlaid with the binding pose of a known potent GRK2 inhibitor, Takeda103A, a library of hybrid inhibitors was developed. This campaign produced several compds. possessing high potency and selectivity for GRK2 over other GRK subfamilies, PKA, and ROCK1. The most selective compd., 12n (I) (CCG-224406), had an IC50 for GRK2 of 130 nM, >700-fold selectivity over other GRK subfamilies, and no detectable inhibition of ROCK1. Four of the new inhibitors were crystd. with GRK2 to give mol. insights into the binding and kinase selectivity of this class of inhibitors.
- 251Okawa, T.; Aramaki, Y.; Yamamoto, M.; Kobayashi, T.; Fukumoto, S.; Toyoda, Y.; Henta, T.; Hata, A.; Ikeda, S.; Kaneko, M.; Hoffman, I. D.; Sang, B. C.; Zou, H.; Kawamoto, T. Design, synthesis, and evaluation of the highly selective and potent G-protein-coupled receptor kinase 2 (GRK2) inhibitor for the potential treatment of heart failure. J. Med. Chem. 2017, 60, 6942– 6990, DOI: 10.1021/acs.jmedchem.7b00443[ACS Full Text], [CAS], Google Scholar251https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFGitbjF&md5=6077a12ddcbd4454ccfc4d55c65c5a61Design, Synthesis, and Evaluation of the Highly Selective and Potent G-Protein-Coupled Receptor Kinase 2 (GRK2) Inhibitor for the Potential Treatment of Heart FailureOkawa, Tomohiro; Aramaki, Yoshio; Yamamoto, Mitsuo; Kobayashi, Toshitake; Fukumoto, Shoji; Toyoda, Yukio; Henta, Tsutomu; Hata, Akito; Ikeda, Shota; Kaneko, Manami; Hoffman, Isaac D.; Sang, Bi-Ching; Zou, Hua; Kawamoto, TetsujiJournal of Medicinal Chemistry (2017), 60 (16), 6942-6990CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A novel class of therapeutic drug candidates for heart failure, highly potent and selective GRK2 inhibitors, exhibit potentiation of β-adrenergic signaling in vitro studies. Hydrazone deriv. and 1,2,4-triazole deriv. were identified as hit compds. by HTS. New scaffold generation and SAR studies of all parts resulted in a 4-methyl-1,2,4-triazole deriv. with an N-benzylcarboxamide moiety with highly potent activity towards GRK2, and selectivity over other kinases. In terms of subtype selectivity, these compds. showed enough selectivity against GRK1, 5, 6, 7 with almost equipotent inhibition to GRK3. The medicinal chem. efforts led to the discovery of I (GRK2 IC50 = 18 nM) which was obtained the cocrystal structure with human GRK2 and an inhibitor of GRK2 that potentiates β-adrenergic receptor (βAR)-mediated cAMP accumulation and prevents internalization of βARs in β2AR-expressing HEK293 cells treated with isoproterenol. Therefore, I appears to be a novel class of therapeutic for heart failure treatment.
- 252Razani, B.; Reichardt, A. D.; Cheng, G. Non-canonical NF-κB signaling activation and regulation: principles and perspectives. Immunol Rev. 2011, 244, 44– 54, DOI: 10.1111/j.1600-065X.2011.01059.x[Crossref], [PubMed], [CAS], Google Scholar252https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFagsL%252FK&md5=b4b7e40a5437602ea0a61aaa5577e1f3Non-canonical NF-κB signaling activation and regulation: principles and perspectivesRazani, Bahram; Reichardt, Anna Devi; Cheng, GenhongImmunological Reviews (2011), 244 (1), 44-54CODEN: IMRED2; ISSN:1600-065X. (Wiley-Blackwell)A review. Nuclear-factor κB (NF-κB) transcription factors are activated by a wide variety of stimuli in diverse cell types and control key aspects of immune function and development. Receptor-mediated activation of NF-κB appears to occur through two distinct signaling pathways termed as the canonical and non-canonical NF-κB pathways. Although much work has demonstrated the physiol. importance of non-canonical NF-κB signaling to immunity and its involvement in diverse pathologies, such as cancers and autoimmune disease, the architecture and regulation of the pathway is only beginning to be understood. The non-canonical pathway appears to be activated by a select set of receptors within the tumor necrosis factor superfamily, and we discuss the mol. mechanisms that connect ligation of these receptors to pathway activation. It has become increasingly clear that the key regulatory step of the pathway involves modulation of the post-translational degrdn. of NF-κB-inducing kinase (NIK), the central activating kinase of non-canonical NF-κB signaling. How NIK post-translational stability is controlled before and after receptor ligation is an important aspect of understanding non-canonical NF-κB signaling. Furthermore, how release of NF-κB dimers downstream of the pathway's activation is actually connected to its identified physiol. and pathol. roles is a key remaining question in the field.
- 253Ren, X.; Li, X.; Jia, L.; Chen, D.; Hou, H.; Rui, L.; Zhao, Y.; Chen, Z. A small-molecule inhibitor of NF-κB-inducing kinase (NIK) protects liver from toxin-induced inflammation, oxidative stress, and injury. FASEB J. 2017, 31, 711– 718, DOI: 10.1096/fj.201600840R[Crossref], [PubMed], [CAS], Google Scholar253https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXpsleit78%253D&md5=84f05fa8fdf2fcfe79d167827ceea738A small-molecule inhibitor of NF-κB-inducing kinase (NIK) protects liver from toxin-induced inflammation, oxidative stress, and injuryRen, Xiaomeng; Li, Xinzhi; Jia, Linna; Chen, Deheng; Hou, Hai; Rui, Liangyou; Zhao, Yujun; Chen, ZhengFASEB Journal (2017), 31 (2), 711-718CODEN: FAJOEC; ISSN:0892-6638. (Federation of American Societies for Experimental Biology)Potent and selective chem. probes are valuable tools for discovery of novel treatments for human diseases. NF-κB-inducing kinase (NIK) is a key trigger in the development of liver injury and fibrosis. Whether inhibition of NIK activity by chem. probes ameliorates liver inflammation and injury is largely unknown. In this study, a small-mol. inhibitor of NIK, B022, was found to be a potent and selective chem. probe for liver inflammation and injury. B022 inhibited the NIK signaling pathway, including NIK-induced p100-to-p52 processing and inflammatory gene expression, both in vitro and in vivo. Furthermore, in vivo administration of B022 protected against not only NIK but also CCl4-induced liver inflammation and injury. Our data suggest that inhibition of NIK is a novel strategy for treatment of liver inflammation, oxidative stress, and injury.
- 254Castanedo, G. M.; Blaquiere, N.; Beresini, M.; Bravo, B.; Brightbill, H.; Chen, J.; Cui, H. F.; Eigenbrot, C.; Everett, C.; Feng, J.; Godemann, R.; Gogol, E.; Hymowitz, S.; Johnson, A.; Kayagaki, N.; Kohli, P. B.; Knuppel, K.; Kraemer, J.; Kruger, S.; Loke, P.; McEwan, P.; Montalbetti, C.; Roberts, D. A.; Smith, M.; Steinbacher, S.; Sujatha-Bhaskar, S.; Takahashi, R.; Wang, X.; Wu, L. C.; Zhang, Y.; Staben, S. T. Structure-based design of tricyclic NF-κB inducing kinase (NIK) inhibitors that have high selectivity over Phosphoinositide-3-kinase (PI3K). J. Med. Chem. 2017, 60, 627– 640, DOI: 10.1021/acs.jmedchem.6b01363[ACS Full Text], [CAS], Google Scholar254https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitFCgs7bK&md5=316b70f51a5b800ba810082d0b3862daStructure-Based Design of Tricyclic NF-κB Inducing Kinase (NIK) Inhibitors That Have High Selectivity over Phosphoinositide-3-kinase (PI3K)Castanedo, Georgette M.; Blaquiere, Nicole; Beresini, Maureen; Bravo, Brandon; Brightbill, Hans; Chen, Jacob; Cui, Hai-Feng; Eigenbrot, Charles; Everett, Christine; Feng, Jianwen; Godemann, Robert; Gogol, Emily; Hymowitz, Sarah; Johnson, Adam; Kayagaki, Nobuhiko; Kohli, Pawan Bir; Knuppel, Kathleen; Kraemer, Joachim; Kruger, Susan; Loke, Pui; McEwan, Paul; Montalbetti, Christian; Roberts, David A.; Smith, Myron; Steinbacher, Stefan; Sujatha-Bhaskar, Swathi; Takahashi, Ryan; Wang, Xiaolu; Wu, Lawren C.; Zhang, Yamin; Staben, Steven T.Journal of Medicinal Chemistry (2017), 60 (2), 627-640CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The authors report a structure-guided optimization of a novel series of NF-κB inducing kinase (NIK) inhibitors. Starting from a modestly potent, low mol. wt. lead, activity was improved by designing a type I1/2 binding mode that accessed a back pocket past the methionine-471 gatekeeper. Divergent binding modes in NIK and PI3K were used to dampen PI3K-inhibition while maintaining NIK inhibition within these series. Potent compds. were discovered that selectively inhibit the nuclear translocation of NF-kB2 (p52/REL-B) but not canonical NF-kB1 (REL-A/p50).
- 255Blaquiere, N.; Castanedo, G. M.; Burch, J. D.; Berezhkovskiy, L. M.; Brightbill, H.; Brown, S.; Chan, C.; Chiang, P. C.; Crawford, J. J.; Dong, T.; Fan, P.; Feng, J.; Ghilardi, N.; Godemann, R.; Gogol, E.; Grabbe, A.; Hole, A. J.; Hu, B.; Hymowitz, S. G.; Alaoui Ismaili, M. H.; Le, H.; Lee, P.; Lee, W.; Lin, X.; Liu, N.; McEwan, P. A.; McKenzie, B.; Silvestre, H. L.; Suto, E.; Sujatha-Bhaskar, S.; Wu, G.; Wu, L. C.; Zhang, Y.; Zhong, Z.; Staben, S. T. Scaffold-hopping approach to discover potent, selective, and efficacious inhibitors of NF-κB inducing kinase. J. Med. Chem. 2018, 61, 6801– 6813, DOI: 10.1021/acs.jmedchem.8b00678[ACS Full Text], [CAS], Google Scholar255https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXht1Snu73P&md5=5ff01b23d827b3d96078a17fff885aeaScaffold-Hopping Approach To Discover Potent, Selective, and Efficacious Inhibitors of NF-κB Inducing KinaseBlaquiere, Nicole; Castanedo, Georgette M.; Burch, Jason D.; Berezhkovskiy, Leonid M.; Brightbill, Hans; Brown, Suzanne; Chan, Connie; Chiang, Po-Chang; Crawford, James J.; Dong, Teresa; Fan, Peter; Feng, Jianwen; Ghilardi, Nico; Godemann, Robert; Gogol, Emily; Grabbe, Alice; Hole, Alison J.; Hu, Baihua; Hymowitz, Sarah G.; Alaoui Ismaili, Moulay Hicham; Le, Hoa; Lee, Patrick; Lee, Wyne; Lin, Xingyu; Liu, Ning; McEwan, Paul A.; McKenzie, Brent; Silvestre, Hernani L.; Suto, Eric; Sujatha-Bhaskar, Swathi; Wu, Guosheng; Wu, Lawren C.; Zhang, Yamin; Zhong, Zoe; Staben, Steven T.Journal of Medicinal Chemistry (2018), 61 (15), 6801-6813CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)NF-κB-inducing kinase (NIK) is a protein kinase central to the noncanonical NF-κB pathway downstream from multiple TNF receptor family members, including BAFF, which has been assocd. with B cell survival and maturation, dendritic cell activation, secondary lymphoid organ development, and bone metab. We report herein the discovery of lead chem. series of NIK inhibitors that were identified through a scaffold-hopping strategy using structure-based design. Electronic and steric properties of lead compds. were modified to address glutathione conjugation and amide hydrolysis. These highly potent compds. exhibited selective inhibition of LTβR-dependent p52 translocation and transcription of NF-κB2 related genes. Compd. 4f is shown to have a favorable pharmacokinetic profile across species and to inhibit BAFF-induced B cell survival in vitro and reduce splenic marginal zone B cells in vivo.
- 256Brightbill, H. D.; Suto, E.; Blaquiere, N.; Ramamoorthi, N.; Sujatha-Bhaskar, S.; Gogol, E. B.; Castanedo, G. M.; Jackson, B. T.; Kwon, Y. C.; Haller, S.; Lesch, J.; Bents, K.; Everett, C.; Kohli, P. B.; Linge, S.; Christian, L.; Barrett, K.; Jaochico, A.; Berezhkovskiy, L. M.; Fan, P. W.; Modrusan, Z.; Veliz, K.; Townsend, M. J.; DeVoss, J.; Johnson, A. R.; Godemann, R.; Lee, W. P.; Austin, C. D.; McKenzie, B. S.; Hackney, J. A.; Crawford, J. J.; Staben, S. T.; Alaoui Ismaili, M. H.; Wu, L. C.; Ghilardi, N. NF-κB inducing kinase is a therapeutic target for systemic lupus erythematosus. Nat. Commun. 2018, 9, 179, DOI: 10.1038/s41467-017-02672-0[Crossref], [PubMed], [CAS], Google Scholar256https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1Mvgtlylug%253D%253D&md5=41a91514e1f4e8b2b44912ba6d6a4788NF-κB inducing kinase is a therapeutic target for systemic lupus erythematosusBrightbill Hans D; Sujatha-Bhaskar Swathi; Gogol Emily B; Jackson Benjamin T; Christian Laura; Wu Lawren C; Ghilardi Nico; Suto Eric; Kwon Youngsu C; Lesch Justin; DeVoss Jason; Lee Wyne P; McKenzie Brent S; Blaquiere Nicole; Castanedo Georgette M; Crawford James J; Staben Steven T; Ramamoorthi Nandhini; Townsend Michael J; Haller Susan; Austin Cary D; Bents Karin; Linge Sandra; Godemann Robert; Everett Christine; Kohli Pawan Bir; Barrett Kathy; Johnson Adam R; Alaoui Ismaili Moulay H; Jaochico Allan; Berezhkovskiy Leonid M; Fan Peter W; Modrusan Zora; Veliz Kelli; Hackney Jason ANature communications (2018), 9 (1), 179 ISSN:.NF-κB-inducing kinase (NIK) mediates non-canonical NF-κB signaling downstream of multiple TNF family members, including BAFF, TWEAK, CD40, and OX40, which are implicated in the pathogenesis of systemic lupus erythematosus (SLE). Here, we show that experimental lupus in NZB/W F1 mice can be treated with a highly selective and potent NIK small molecule inhibitor. Both in vitro as well as in vivo, NIK inhibition recapitulates the pharmacological effects of BAFF blockade, which is clinically efficacious in SLE. Furthermore, NIK inhibition also affects T cell parameters in the spleen and proinflammatory gene expression in the kidney, which may be attributable to inhibition of OX40 and TWEAK signaling, respectively. As a consequence, NIK inhibition results in improved survival, reduced renal pathology, and lower proteinuria scores. Collectively, our data suggest that NIK inhibition is a potential therapeutic approach for SLE.
- 257Zhu, Y.; Ma, Y.; Zu, W.; Song, J.; Wang, H.; Zhong, Y.; Li, H.; Zhang, Y.; Gao, Q.; Kong, B.; Xu, J.; Jiang, F.; Wang, X.; Li, S.; Liu, C.; Liu, H.; Lu, T.; Chen, Y. Identification of N-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine derivatives as novel, potent, and selective NF-κB inducing kinase (NIK) inhibitors for the treatment of psoriasis. J. Med. Chem. 2020, 63, 6748– 6773, DOI: 10.1021/acs.jmedchem.0c00055[ACS Full Text], [CAS], Google Scholar257https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtVKnt7vN&md5=159d4bb74b1d7c3111aaa55cba35f64cIdentification of N-Phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine Derivatives as Novel, Potent, and Selective NF-κB Inducing Kinase (NIK) Inhibitors for the Treatment of PsoriasisZhu, Yuqin; Ma, Yuxiang; Zu, Weidong; Song, Jianing; Wang, Hua; Zhong, You; Li, Hongmei; Zhang, Yanmin; Gao, Qianqian; Kong, Bo; Xu, Junyu; Jiang, Fei; Wang, Xinren; Li, Shuwen; Liu, Chenhe; Liu, Haichun; Lu, Tao; Chen, YadongJournal of Medicinal Chemistry (2020), 63 (13), 6748-6773CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of N-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine derivs. with NF-κB inducing kinase (NIK) inhibitory activity were obtained through structure-based drug design and synthetic chem. Among them, 4-(3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4-morpholinophenyl)-2-(thiazol-2-yl)but-3-yn-2-ol (12f)(I) was identified as a highly potent NIK inhibitor, along with satisfactory selectivity. The pharmacokinetics of 12f and its ability to inhibit interleukin 6 secretion in BEAS-2B cells were better than compd. 1 developed by Amgen. Oral administration of different doses of 12f in an imiquimod-induced psoriasis mouse model showed effective alleviation of psoriasis, including invasive erythema, swelling, skin thickening, and scales. The underlying pathol. mechanism involved attenuation of proinflammatory cytokine and chemokine gene expression, and the infiltration of macrophages after the treatment of 12f. This work provides a foundation for the development of NIK inhibitors, highlighting the potential of developing NIK inhibitors as a new strategy for the treatment of psoriasis.
- 258Li, Z.; Li, X.; Su, M. B.; Gao, L. X.; Zhou, Y. B.; Yuan, B.; Lyu, X.; Yan, Z.; Hu, C.; Zhang, H.; Luo, C.; Chen, Z.; Li, J.; Zhao, Y. Discovery of a potent and selective NF-κB-inducing kinase (NIK) inhibitor that has anti-inflammatory effects in vitro and in vivo. J. Med. Chem. 2020, 63, 4388– 4407, DOI: 10.1021/acs.jmedchem.0c00396[ACS Full Text], [CAS], Google Scholar258https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXlvVGmt74%253D&md5=40edf4070f12b964303d3ed8e72dad9fDiscovery of a Potent and Selective NF-κB-Inducing Kinase (NIK) Inhibitor That Has Anti-inflammatory Effects in Vitro and in VivoLi, Zhiqiang; Li, Xinzhi; Su, Ming-Bo; Gao, Li-Xin; Zhou, Yu-Bo; Yuan, Bingchuan; Lyu, Xilin; Yan, Ziqin; Hu, Chujiao; Zhang, Hao; Luo, Cheng; Chen, Zheng; Li, Jia; Zhao, YujunJournal of Medicinal Chemistry (2020), 63 (8), 4388-4407CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The overexpression of NIK plays a crit. role in liver inflammatory diseases. Treatment of such diseases with small-mol. NIK inhibitors is a reasonable but underexplored approach. In this paper, we reported the discovery of a potent and selective NIK inhibitor 46 (XT2). 46 inhibited the NIK kinase with an IC50 value of 9.1 nM in vitro, and it also potently suppressed NIK activities in intact cells. In isogenic primary hepatocytes, treatment of 46 efficiently suppressed the expressions of NIK-induced genes. 46 was orally bioavailable in mice with moderate systemic exposure. In a NIK-assocd. mouse liver inflammation model, 46 suppressed CCl4-induced upregulation of ALT, a key biomarker of acute liver injury. 46 also decreased immune cell infiltration into the injured liver tissue. Overall, these studies provide examples that an NIK inhibitor is able to suppress toxin-induced liver inflammations, which indicates its therapeutic potentials for the treatment of liver inflammatory diseases.
- 259Liao, C.; Yao, R. S. Diversity evolution and jump of Polo-like kinase 1 inhibitors. Sci. China: Chem. 2013, 56, 1392– 1401, DOI: 10.1007/s11426-013-4963-0[Crossref], [CAS], Google Scholar259https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtlCqsrfJ&md5=3c43ec202554cda7cf7114fa07ac84aeDiversity evolution and jump of Polo-like kinase 1 inhibitorsLiao, Chenzhong; Yao, Ri ShengScience China: Chemistry (2013), 56 (10), 1392-1401CODEN: SCCCCS; ISSN:1869-1870. (Science China Press)A review. Polo-like kinase 1 (Plk1), a member of a family of serine/threonine kinases, is an attractive target for the development of anticancer drugs because it is involved in the regulation of cell-cycle progression and cytokinesis. This kinase provides two pockets for developing Plk1 inhibitors: the N-terminal catalytic domain (NCD) and the polo-box domain (PBD). For both of the two pockets, some natural products were identified as Plk1 inhibitors and some synthetic Plk1 inhibitors were developed by mimicking ATP and phosphopeptides, natural products binding to NCD and PBD resp. This article not only reviews the progression of Plk1 inhibitors binding to these two pockets, but also discusses diversity evolution and jump in the process of drug development using Plk1 inhibitors as examples and how they impact on drug design and pharmacophore modeling.
- 260Lv, X.; Yang, X.; Zhan, M. M.; Cao, P.; Zheng, S.; Peng, R.; Han, J.; Xie, Z.; Tu, Z.; Liao, C. Structure-based design and SAR development of novel selective polo-like kinase 1 inhibitors having the tetrahydropteridin scaffold. Eur. J. Med. Chem. 2019, 184, 111769, DOI: 10.1016/j.ejmech.2019.111769[Crossref], [PubMed], [CAS], Google Scholar260https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvF2rsbzN&md5=bd6caed64a3e9587a7dc670888a4c521Structure-based design and SAR development of novel selective polo-like kinase 1 inhibitors having the tetrahydropteridin scaffoldLv, Xiao; Yang, Xiaoxiao; Zhan, Mei-Miao; Cao, Peichang; Zheng, Shihong; Peng, Ruijun; Han, Jihong; Xie, Zhouling; Tu, Zhengchao; Liao, ChenzhongEuropean Journal of Medicinal Chemistry (2019), 184 (), 111769CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)Polo-like kinase 1 (Plk1) is a validated target for the treatment of cancer. In this report, by analyzing amino acid residue differences among the ATP-binding pockets of Plk1, Plk2 and Plk3, novel selective Plk1 inhibitors were designed based on BI 2536 and BI 6727, two Plk1 inhibitors in clin. studies for cancer treatments. The Plk1 inhibitors reported herein have more potent inhibition against Plk1 and better isoform selectivity in the Plk family than these two lead compds. In addn., by introducing a hydroxyl group, our compds. have significantly improved soly. and may target specific polar residues Arg57, Glu69 and Arg134 of Plk1. Moreover, most of our compds. exhibited antitumor activities in the nanomolar range against several cancer cell lines in the MTT assay. Through this structure-based design strategy and SAR study, a few promising selective Plk1 inhibitors having the tetrahydropteridin scaffold, for example, L34(I), were identified and could be for further anticancer research.
- 261Huang, X.; Xie, Z.; Liao, C. Developing polo-like kinase 1 inhibitors. Future Med. Chem. 2020, 12, 869– 871, DOI: 10.4155/fmc-2020-0055[Crossref], [PubMed], [CAS], Google Scholar261https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXpslygtro%253D&md5=da8b26c3c3205058cf25b5203e4802e9Developing polo-like kinase 1 inhibitorsHuang, Xufeng; Xie, Zhouling; Liao, ChenzhongFuture Medicinal Chemistry (2020), 12 (10), 869-871CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)There is no expanded citation for this reference.
- 262Cozza, G.; Salvi, M. The acidophilic kinases PLK2 and PLK3: structure, substrate targeting and inhibition. Curr. Protein Pept. Sci. 2018, 19, 728– 745, DOI: 10.2174/1389203719666180124095405[Crossref], [PubMed], [CAS], Google Scholar262https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXht1yku7rK&md5=97cbaf75a8ae18438b30485bafd712faThe Acidophilic Kinases PLK2 and PLK3: Structure, Substrate Targeting and InhibitionCozza, Giorgio; Salvi, MauroCurrent Protein and Peptide Science (2018), 19 (8), 728-745CODEN: CPPSCM; ISSN:1389-2037. (Bentham Science Publishers Ltd.)A review. PLK2 and PLK3 are two closely related acidophilic kinases belonging to the Polo-like kinases (PLKs), a family of five members in mammals with a central role in cell cycle and related events. PLK1 is the most investigated enzyme from both physiol. and pharmaceutical points of view, however, several specialized cellular functions of PLK2 and PLK3 have been recently discovered paving the way to deepened studies on their biol. roles and their feasible selection as future therapeutic targets. Our review aims to provide a summarized view of the current knowledge regarding PLK2 and PLK3 kinases, including substrate specificity and signaling pathways directly affected by these kinases. Finally, an overview of PLK2 and PLK3 pharmacol. regulation and perspectives in future achievements are proposed.
- 263Hu, Z.; Xu, Z.; Liao, X.; Yang, X.; Dong, C.; Luk, K.; Jin, A.; Lu, H. Polo-like kinase 2 acting as a promoter in human tumor cells with an abundance of TAp73. OncoTargets Ther. 2015, 8, 3475– 3488, DOI: 10.2147/OTT.S90302[Crossref], [PubMed], [CAS], Google Scholar263https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXls1yms7c%253D&md5=0b0d456be9526a4b1b4ecdd42a49cd1bPolo-like kinase 2 acting as a promoter in human tumor cells with an abundance of TAp73 ZhengBo Hu1,* ZunYing Xu1,* XiaoHongHu, Zheng Bo; Xu, Zun Ying; Liao, Xiao Hong; Yang, Xiao; Dong, Cao; Luk, Kua Di; Jin, An Min; Lu, HaiOncoTargets and Therapy (2015), 8 (), 3475-3488CODEN: OTNHAZ; ISSN:1178-6930. (Dove Medical Press Ltd.)Background: TAp73, a member of the p53 tumor suppressor family, is frequently overexpressed in malignant tumors in humans. TAp73 abundance and phosphorylation modification result in variations in transcriptional activity. In a previous study, we found that the antitumor function of TAp73 was reactivated by dephosphorylation in head and neck squamous cell carcinomas. Polo-like kinase 2 (PLK2) displayed a close relationship with the p53 family in affecting the fate of cells. Herein, we investigate the hypothesis that PLK2 phosphorylates TAp73 and inhibits TAp73 function. Materials and methods: Head and neck squamous cell carcinoma cell lines and osteosarcoma cell lines were used as natural models of the different expression levels of TAp73. Phosphorylation predictor software Scansite 3.0 and the predictor GPS-polo 1.0 were used to analyze the phosphorylation sites. Coimmunopptn., phosphor-tag Western blot, metabolic labeling, and indirect immunofluorescence assays were used to det. the interactions between PLK2 and TAp73. TAp73 activity was assessed by Western blot and reverse transcription polymerase chain reaction, which we used to detect P21 and PUMA, both downstream genes of TAp73. The physiol. effects of PLK2 cross talk with TAp73 on cell cycle progress and apoptosis were obsd. by flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling assays. Results: PLK2 binds to and phosphorylates TAp73. PLK2 phosphorylates TAp73 at residue Ser48 and prohibits TAp73 translocation to the nucleus. Addnl., PLK2 inhibition combined with a DNA-damaging drug upregulated p21 and PUMA mRNA expression to a greater extent than DNA-damaging drug treatment alone. Inhibiting PLK2 in TAp73-enriched cells strengthened the effects of the DNA-damaging drug on both G1 phase arrest and apoptosis. Pretreatment with TAp73-siRNA weakened these effects. Conclusion: These findings reveal a novel PLK2 function (catalyzed phosphorylation of TAp73) which suppresses TAp73 functions. PLK2 promotes the survival of human tumor cells, a novel insight into the workings of malignant tumors characterized by TAp73 overexpression, and one that could speed the development of therapies.
- 264Zhan, M. M.; Yang, Y.; Luo, J.; Zhang, X. X.; Xiao, X.; Li, S.; Cheng, K.; Xie, Z.; Tu, Z.; Liao, C. Design, synthesis, and biological evaluation of novel highly selective polo-like kinase 2 inhibitors based on the tetrahydropteridin chemical scaffold. Eur. J. Med. Chem. 2018, 143, 724– 731, DOI: 10.1016/j.ejmech.2017.11.058[Crossref], [PubMed], [CAS], Google Scholar264https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFejt7jJ&md5=833fc543d15f8d79752cfb37975920d3Design, synthesis, and biological evaluation of novel highly selective polo-like kinase 2 inhibitors based on the tetrahydropteridin chemical scaffoldZhan, Mei-Miao; Yang, Yang; Luo, Jinfeng; Zhang, Xing-Xing; Xiao, Xuan; Li, Shiyu; Cheng, Kai; Xie, Zhouling; Tu, Zhengchao; Liao, ChenzhongEuropean Journal of Medicinal Chemistry (2018), 143 (), 724-731CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)Aminosulfonylphenylamino- and indolyl-substituted tetrahydropteridines such as I were prepd. as selective inhibitors of Polo-like kinase 2 (Plk2) for potential use as antitumor agents. The inhibition of Plk2 and of the related enzymes Plk1 and Plk3 of aminosulfonylphenylamino- and indolyl-substituted tetrahydropteridines and their inhibition of human cancer cell lines was detd.; mol. docking calcns. of selected compds. in the active site of Plk2 were performed. A (methylaminosulfonylphenylamino)tetrahydropteridine (IC50 for Plk2 = 3.40 nM) and I (IC50 for Plk2 = 4.88 nM) were identified as the most active Plk2 inhibitors; I was 12-fold and >900-fold selective for Plk2 over Plk1 and Plk3, resp.
- 265Kofoed, R. H.; Zheng, J.; Ferreira, N.; Lykke-Andersen, S.; Salvi, M.; Betzer, C.; Reimer, L.; Jensen, T. H.; Fog, K.; Jensen, P. H. Polo-like kinase 2 modulates α-synuclein protein levels by regulating its mRNA production. Neurobiol. Dis. 2017, 106, 49– 62, DOI: 10.1016/j.nbd.2017.06.014[Crossref], [PubMed], [CAS], Google Scholar265https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVKntL7F&md5=f68095edcbd07c21522b1ead6f096788Polo-like kinase 2 modulates α-synuclein protein levels by regulating its mRNA productionKofoed, Rikke H.; Zheng, Jin; Ferreira, Nelson; Lykke-Andersen, Soeren; Salvi, Mauro; Betzer, Cristine; Reimer, Lasse; Jensen, Torben Heick; Fog, Karina; Jensen, Poul H.Neurobiology of Disease (2017), 106 (), 49-62CODEN: NUDIEM; ISSN:0969-9961. (Elsevier Inc.)Variations in the α-synuclein-encoding SNCA gene represent the greatest genetic risk factor for Parkinson's disease (PD), and duplications/triplications of SNCA cause autosomal dominant familial PD. These facts closely link brain levels of α-synuclein with the risk of PD, and make lowering α-synuclein levels a therapeutic strategy for the treatment of PD and related synucleinopathies. In this paper, we corroborate previous findings on the ability of overexpressed Polo-like kinase 2 (PLK-2) to decrease cellular α-synuclein, but demonstrate that the process is independent of PLK-2 phosphorylating S129 in α-synuclein because a similar redn. is achieved with the non-phosphorable S129A mutant α-synuclein. Using a specific PLK-2 inhibitor (compd. 37), we demonstrate that endogenous PLK-2 phosphorylates S129 only in some cells, but increases α-synuclein protein levels in all tested cell cultures and brain slices. PLK-2 is found to regulate the transcription of α-synuclein mRNA from both the endogenous mouse SNCA gene and transgenic vectors that only contain the open reading frame. Moreover, we are the first to show that regulation of α-synuclein by PLK-2 is of physiol. importance since 10 days' inhibition of endogenous PLK-2 in wt C57BL/6 mice increases endogenous α-synuclein protein levels. Our findings collectively demonstrate that PLK-2 regulates α-synuclein levels by a previously undescribed transcription-based mechanism. This mechanism is active in cells and brain tissue, opening up for alternative strategies for modulating α-synuclein levels and thereby for the possibility of modifying disease progression in synucleinopaties.
- 266Aubele, D. L.; Hom, R. K.; Adler, M.; Galemmo, R. A.; Bowers, S.; Truong, A. P.; Pan, H.; Beroza, P.; Neitz, R. J.; Yao, N. H.; Lin, M.; Tonn, G.; Zhang, H.; Bova, M. P.; Ren, Z.; Tam, D.; Ruslim, L.; Baker, J.; Diep, L.; Fitzgerald, K.; Hoffman, J.; Motter, R.; Fauss, D.; Tanaka, P.; Dappen, M.; Jagodzinski, J.; Chan, W. M.; Konradi, A. W.; Latimer, L.; Zhu, Y. L.; Sham, H. L.; Anderson, J. P.; Bergeron, M.; Artis, D. R. Selective and brain-permeable Polo-like kinase-2 (Plk-2) inhibitors that reduce -synuclein phosphorylation in rat brain. ChemMedChem 2013, 8, 1295– 1313, DOI: 10.1002/cmdc.201300166[Crossref], [PubMed], [CAS], Google Scholar266https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXpvVensLY%253D&md5=3f5d2981036f440498862c2c85199083Selective and Brain-Permeable Polo-like Kinase-2 (Plk-2) Inhibitors That Reduce α-Synuclein Phosphorylation in Rat BrainAubele, Danielle L.; Hom, Roy K.; Adler, Marc; Galemmo, Robert A., Jr.; Bowers, Simeon; Truong, Anh P.; Pan, Hu; Beroza, Paul; Neitz, R. Jeffrey; Yao, Nanhua; Lin, May; Tonn, George; Zhang, Heather; Bova, Michael P.; Ren, Zhao; Tam, Danny; Ruslim, Lany; Baker, Jeanne; Diep, Linnea; Fitzgerald, Kent; Hoffman, Jennifer; Motter, Ruth; Fauss, Donald; Tanaka, Pearl; Dappen, Michael; Jagodzinski, Jacek; Chan, Wayman; Konradi, Andrei W.; Latimer, Lee; Zhu, Yong L.; Sham, Hing L.; Anderson, John P.; Bergeron, Marcelle; Artis, Dean R.ChemMedChem (2013), 8 (8), 1295-1313CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)Polo-like kinase-2 (Plk-2) has been implicated as the dominant kinase involved in the phosphorylation of α-synuclein in Lewy bodies, which are one of the hallmarks of Parkinson's disease neuropathol. Potent, selective, brain-penetrant inhibitors of Plk-2 were obtained from a structure-guided drug discovery approach driven by the first reported Plk-2-inhibitor complexes. The best of these compds. showed excellent isoform and kinome-wide selectivity, with physicochem. properties sufficient to interrogate the role of Plk-2 inhibition in vivo. One such compd. significantly decreased phosphorylation of α-synuclein in rat brain upon oral administration and represents a useful probe for future studies of this therapeutic avenue toward the potential treatment of Parkinson's disease.
- 267Fitzgerald, K.; Bergeron, M.; Willits, C.; Bowers, S.; Aubele, D. L.; Goldbach, E.; Tonn, G.; Ness, D.; Olaharski, A. Pharmacological inhibition of polo like kinase 2 (PLK2) does not cause chromosomal damage or result in the formation of micronuclei. Toxicol. Appl. Pharmacol. 2013, 269, 1– 7, DOI: 10.1016/j.taap.2013.02.012[Crossref], [PubMed], [CAS], Google Scholar267https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXlvVCnu7g%253D&md5=853686e26e5f21cce4adac193a8198f2Pharmacological inhibition of Polo Like Kinase 2 (PLK2) does not cause chromosomal damage or result in the formation of micronucleiFitzgerald, Kent; Bergeron, Marcelle; Willits, Christopher; Bowers, Simeon; Aubele, Danielle L.; Goldbach, Erich; Tonn, George; Ness, Daniel; Olaharski, AndrewToxicology and Applied Pharmacology (2013), 269 (1), 1-7CODEN: TXAPA9; ISSN:0041-008X. (Elsevier Inc.)Polo Like Kinase 2 (PLK2) phosphorylates α-synuclein and is considered a putative therapeutic target for Parkinson's disease. Several lines of evidence indicate that PLK2 is involved with proper centriole duplication and cell cycle regulation, inhibition of which could impact chromosomal integrity during mitosis. The objectives of the series of expts. presented herein were to assess whether specific inhibition of PLK2 is genotoxic and det. if PLK2 could be considered a tractable pharmacol. target for Parkinson's disease. Several selective PLK2 inhibitors, ELN 582175 and ELN 582646, and their inactive enantiomers, ELN 582176 and ELN 582647, did not significantly increase the no. of micronuclei in the in vitro micronucleus assay. ELN 582646 was administered to male Sprague Dawley rats in an exploratory 14-day study where flow cytometric anal. of peripheral blood identified a dose-dependent increase in the no. of micronucleated reticulocytes. A follow-up investigative study demonstrated that ELN 582646 administered to PLK2 deficient and wildtype mice significantly increased the no. of peripheral micronucleated reticulocytes in both genotypes, suggesting that ELN 582646-induced genotoxicity is not through the inhibition of PLK2. Furthermore, significant redn. of retinal phosphorylated α-synuclein levels was obsd. at three non-genotoxic doses, addnl. data to suggest that pharmacol. inhibition of PLK2 is not the cause of the obsd. genotoxicity. These data, in aggregate, indicate that PLK2 inhibition is a tractable CNS pharmacol. target that does not cause genotoxicity at doses and exposures that engage the target in the sensory retina.
- 268Steegmaier, M.; Hoffmann, M.; Baum, A.; Lenart, P.; Petronczki, M.; Krssak, M.; Gurtler, U.; Garin-Chesa, P.; Lieb, S.; Quant, J.; Grauert, M.; Adolf, G. R.; Kraut, N.; Peters, J. M.; Rettig, W. J. BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo. Curr. Biol. 2007, 17, 316– 322, DOI: 10.1016/j.cub.2006.12.037[Crossref], [PubMed], [CAS], Google Scholar268https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhvVyjtbg%253D&md5=49807e335b4ab8cf8209b55597fc7b4eBI 2536, a Potent and Selective Inhibitor of Polo-like Kinase 1, Inhibits Tumor Growth In VivoSteegmaier, Martin; Hoffmann, Matthias; Baum, Anke; Lenart, Peter; Petronczki, Mark; Krssak, Martin; Guertler, Ulrich; Garin-Chesa, Pilar; Lieb, Simone; Quant, Jens; Grauert, Matthias; Adolf, Guenther R.; Kraut, Norbert; Peters, Jan-Michael; Rettig, Wolfgang J.Current Biology (2007), 17 (4), 316-322CODEN: CUBLE2; ISSN:0960-9822. (Cell Press)Fine-mapping of the cell-division cycle, notably the identification of mitotic kinase signaling pathways, provides novel opportunities for cancer-drug discovery. As a key regulator of multiple steps during mitotic progression across eukaryotic species, the serine/threonine-specific Polo-like kinase 1 (Plk1) is highly expressed in malignant cells and serves as a neg. prognostic marker in specific human cancer types . Here, we report the discovery of a potent small-mol. inhibitor of mammalian Plk1, BI 2536, which inhibits Plk1 enzyme activity at low nanomolar concns. The compd. potently causes a mitotic arrest and induces apoptosis in human cancer cell lines of diverse tissue origin and oncogenome signature. BI 2536 inhibits growth of human tumor xenografts in nude mice and induces regression of large tumors with well-tolerated i.v. dose regimens. In treated tumors, cells arrest in prometaphase, accumulate phosphohistone H3, and contain aberrant mitotic spindles. This mitotic arrest is followed by a surge in apoptosis, detectable by immunohistochem. and noninvasive optical and magnetic resonance imaging. For addressing the therapeutic potential of Plk1 inhibition, BI 2536 has progressed into clin. studies in patients with locally advanced or metastatic cancers.
- 269Cabrera, D. G.; Horatscheck, A.; Wilson, C. R.; Basarab, G.; Eyermann, C. J.; Chibale, K. Plasmodial kinase inhibitors: license to cure?. J. Med. Chem. 2018, 61, 8061– 8077, DOI: 10.1021/acs.jmedchem.8b00329[ACS Full Text], [CAS], Google Scholar269https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXps12ltrg%253D&md5=274df0d629d4cf4fcb7a158e9e72aaabPlasmodial Kinase Inhibitors: License to Cure?Cabrera, Diego Gonzalez; Horatscheck, Andre; Wilson, Colin R.; Basarab, Greg; Eyermann, Charles J.; Chibale, KellyJournal of Medicinal Chemistry (2018), 61 (18), 8061-8077CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Advances in the genetics, function, and stage-specificity of Plasmodium kinases has driven robust efforts to identify targets for the design of antimalarial therapies. Reverse genomics following phenotypic screening against Plasmodia or related parasites has uncovered vulnerable kinase targets including PI4K, PKG, and GSK-3, an approach bolstered by access to human disease-directed kinase libraries. Alternatively, screening compd. libraries against Plasmodium kinases has successfully led to inhibitors with antiplasmodial activity. As with other therapeutic areas, optimizing compd. ADMET and PK properties in parallel with target inhibitory potency and whole cell activity becomes paramount toward advancing compds. as clin. candidates. These and other considerations will be discussed in the context of progress achieved toward deriving important, novel mode-of-action kinase-inhibiting antimalarial medicines.
- 270McNamara, C. W.; Lee, M. C.; Lim, C. S.; Lim, S. H.; Roland, J.; Simon, O.; Yeung, B. K.; Chatterjee, A. K.; McCormack, S. L.; Manary, M. J.; Zeeman, A. M.; Dechering, K. J.; Kumar, T. S.; Henrich, P. P.; Gagaring, K.; Ibanez, M.; Kato, N.; Kuhen, K. L.; Fischli, C.; Nagle, A.; Rottmann, M.; Plouffe, D. M.; Bursulaya, B.; Meister, S.; Rameh, L.; Trappe, J.; Haasen, D.; Timmerman, M.; Sauerwein, R. W.; Suwanarusk, R.; Russell, B.; Renia, L.; Nosten, F.; Tully, D. C.; Kocken, C. H.; Glynne, R. J.; Bodenreider, C.; Fidock, D. A.; Diagana, T. T.; Winzeler, E. A. Targeting Plasmodium PI(4)K to eliminate malaria. Nature 2013, 504, 248– 253, DOI: 10.1038/nature12782[Crossref], [PubMed], [CAS], Google Scholar270https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFaqsLzP&md5=9ed8f3e41d257bb4535b4c813abd54cfTargeting Plasmodium PI(4)K to eliminate malariaMcNamara, Case W.; Lee, Marcus C. S.; Lim, Chek Shik; Lim, Siau Hoi; Roland, Jason; Nagle, Advait; Simon, Oliver; Yeung, Bryan K. S.; Chatterjee, Arnab K.; McCormack, Susan L.; Manary, Micah J.; Zeeman, Anne-Marie; Dechering, Koen J.; Kumar, T. R. Santha; Henrich, Philipp P.; Gagaring, Kerstin; Ibanez, Maureen; Kato, Nobutaka; Kuhen, Kelli L.; Fischli, Christoph; Rottmann, Matthias; Plouffe, David M.; Bursulaya, Badry; Meister, Stephan; Rameh, Lucia; Trappe, Joerg; Haasen, Dorothea; Timmerman, Martijn; Sauerwein, Robert W.; Suwanarusk, Rossarin; Russell, Bruce; Renia, Laurent; Nosten, Francois; Tully, David C.; Kocken, Clemens H. M.; Glynne, Richard J.; Bodenreider, Christophe; Fidock, David A.; Diagana, Thierry T.; Winzeler, Elizabeth A.Nature (London, United Kingdom) (2013), 504 (7479), 248-253CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here the authors identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compd. class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax, and inhibit liver-stage hypnozoites in the simian parasite P. cynomolgi. The authors show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate. Collectively, the authors' data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria.
- 271Bozdech, Z.; Ferreira, P. E.; Mok, S. A crucial piece in the puzzle of the artemisinin resistance mechanism in Plasmodium falciparum. Trends Parasitol. 2015, 31, 345– 346, DOI: 10.1016/j.pt.2015.06.004[Crossref], [PubMed], [CAS], Google Scholar271https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFWgsbvO&md5=42949da3589ee312e5f0e74ba2819c75A crucial piece in the puzzle of the artemisinin resistance mechanism in Plasmodium falciparumBozdech, Zbynek; Ferreira, Pedro E.; Mok, SachelTrends in Parasitology (2015), 31 (8), 345-346CODEN: TPRACT; ISSN:1471-4922. (Elsevier Ltd.)The spread of resistance of malaria infections to artemisinin is a major concern for the future. The Plasmodium falciparum phosphatidylinositol-3-kinase (PfPI3K) may be a potential target of artemisinin and effector of resistance. This could be mediated by the Kelch13 protein, the mol. marker of resistance that modulates PfPI3K ubiquitination.
- 272Younis, Y.; Douelle, F.; Feng, T. S.; Cabrera, D. G.; Le Manach, C.; Nchinda, A. T.; Duffy, S.; White, K. L.; Shackleford, D. M.; Morizzi, J.; Mannila, J.; Katneni, K.; Bhamidipati, R.; Zabiulla, K. M.; Joseph, J. T.; Bashyam, S.; Waterson, D.; Witty, M. J.; Hardick, D.; Wittlin, S.; Avery, V.; Charman, S. A.; Chibale, K. 3,5-diaryl-2-aminopyridines as a novel class of orally active antimalarials demonstrating single dose cure in mice and clinical candidate potential. J. Med. Chem. 2012, 55, 3479– 3487, DOI: 10.1021/jm3001373[ACS Full Text], [CAS], Google Scholar272https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjt1SqtL4%253D&md5=6f8bd20049550b82b81b3c7c5b0b9aae3,5-Diaryl-2-aminopyridines as a Novel Class of Orally Active Antimalarials Demonstrating Single Dose Cure in Mice and Clinical Candidate PotentialYounis, Yassir; Douelle, Frederic; Feng, Tzu-Shean; Cabrera, Diego Gonzalez; Manach, Claire Le; Nchinda, Aloysius T.; Duffy, Sandra; White, Karen L.; Shackleford, David M.; Morizzi, Julia; Mannila, Janne; Katneni, Kasiram; Bhamidipati, Ravi; Zabiulla, K. Mohammed; Joseph, Jayan T.; Bashyam, Sridevi; Waterson, David; Witty, Michael J.; Hardick, David; Wittlin, Sergio; Avery, Vicky; Charman, Susan A.; Chibale, KellyJournal of Medicinal Chemistry (2012), 55 (7), 3479-3487CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A novel class of orally active antimalarial 3,5-diaryl-2-aminopyridines has been identified from phenotypic whole cell high-throughput screening of a com. available SoftFocus kinase library. The compds. were evaluated in vitro for their antiplasmodial activity against K1 (chloroquine and drug-resistant strain) and NF54 (chloroquine-susceptible strain) as well as for their cytotoxicity. Synthesis and structure-activity studies identified a no. of promising compds. with selective antiplasmodial activity. One of these front-runner compds., I, was equipotent across the two strains (K1 = 25.0 nM, NF54 = 28.0 nM) and superior to chloroquine in the K1 strain (chloroquine IC50 K1 = 194.0 nM). Compd. I completely cured Plasmodium berghei-infected mice with a single oral dose of 30 mg/kg. Dose-response studies generated ED50 and ED90 values of 0.83 and 1.74 mg/kg for 15 in the std. four-dose Peters test. Pharmacokinetic studies in the rat indicated that I has good oral bioavailability (51% at 20 mg/kg) and a reasonable half-life (t1/2 ∼ 7-8 h).
- 273Droucheau, E.; Primot, A.; Thomas, V.; Mattei, D.; Knockaert, M.; Richardson, C.; Sallicandro, P.; Alano, P.; Jafarshad, A.; Baratte, B.; Kunick, C.; Parzy, D.; Pearl, L.; Doerig, C.; Meijer, L. Plasmodium falciparum glycogen synthase kinase-3: molecular model, expression, intracellular localisation and selective inhibitors. Biochim. Biophys. Acta, Proteins Proteomics 2004, 1697, 181– 196, DOI: 10.1016/j.bbapap.2003.11.023[Crossref], [PubMed], [CAS], Google Scholar273https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXitFKlsLw%253D&md5=d7a7289b294d3cb46d28c122bb7e7e5ePlasmodium falciparum glycogen synthase kinase-3: molecular model, expression, intracellular localization and selective inhibitorsDroucheau, Eliane; Primot, Aline; Thomas, Virginie; Mattei, Denise; Knockaert, Marie; Richardson, Chris; Sallicandro, Pina; Alano, Pietro; Jafarshad, Ali; Baratte, Blandine; Kunick, Conrad; Parzy, Daniel; Pearl, Laurence; Doerig, Christian; Meijer, LaurentBiochimica et Biophysica Acta, Proteins and Proteomics (2004), 1697 (1-2), 181-196CODEN: BBAPBW; ISSN:1570-9639. (Elsevier B.V.)A review. Worldwide increasing resistance of Plasmodium falciparum to common antimalarias calls for the urgent identification of new drugs. Glycogen synthase kinase-3 (GSK-3) represents a potential screening target for the identification of such new compds. The authors have cloned PfGSK-3, the P. falciparum gene homolog of GSK-3β. It encodes a 452-amino-acid, 53-kDa protein with an unusual N-terminal extension but a well-conserved catalytic domain. A PfGSK-3 tridimensional homol. model was generated on the basis of the recently crystd. human GSK-3β. It illustrates how the regions involved in the active site, in substrate binding (P+4 phosphate-binding domain) and in activity regulation are highly conserved. Recombinant PfGSK-3 phosphorylates GS-1, a GSK-3-specific peptide substrate, glycogen synthase, recombinant axin, and microtubule-binding protein tau. Neither native nor recombinant PfGSK-3 binds to axin. The expression and intracellular localization of PfGSK-3 have been investigated in the erythrocytic stages. Although PfGSK-3 mRNA is present in similar amts. at all stages, the PfGSK-3 protein is predominantly expressed at the early trophozoite stage. Once synthesized, PfGSK-3 is rapidly transported to the erythrocyte cytoplasm where it assocs. with vesicle-like structures. The physiol. functions of PfGSK-3 for the parasite remain to be elucidated. A series of GSK-3β inhibitors have been tested on both PfGSK-3 and mammalian GSK-3β. Remarkably, these enzymes have shown a partially divergent sensitivity to the compds., suggesting that PfGSK-3 selective compds. might be identified.
- 274Fugel, W.; Oberholzer, A. E.; Gschloessl, B.; Dzikowski, R.; Pressburger, N.; Preu, L.; Pearl, L. H.; Baratte, B.; Ratin, M.; Okun, I.; Doerig, C.; Kruggel, S.; Lemcke, T.; Meijer, L.; Kunick, C. 3,6-Diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitriles are selective inhibitors of Plasmodium falciparum glycogen synthase kinase-3. J. Med. Chem. 2013, 56, 264– 275, DOI: 10.1021/jm301575n[ACS Full Text], [CAS], Google Scholar274https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhsl2lsrzL&md5=841d254e2f6c6e7a62c947f82fabd0923,6-Diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitriles Are Selective Inhibitors of Plasmodium falciparum Glycogen Synthase Kinase-3Fugel, Wiebke; Oberholzer, Anselm Erich; Gschloessl, Bernhard; Dzikowski, Ron; Pressburger, Narkiss; Preu, Lutz; Pearl, Laurence H.; Baratte, Blandine; Ratin, Morgane; Okun, Ilya; Doerig, Christian; Kruggel, Sebastian; Lemcke, Thomas; Meijer, Laurent; Kunick, ConradJournal of Medicinal Chemistry (2013), 56 (1), 264-275CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Plasmodium falciparum is the infective agent responsible for malaria tropica. The glycogen synthase kinase-3 of the parasite (PfGSK-3) was suggested as a potential biol. target for novel antimalarial drugs. Starting from hit structures identified in a high-throughput screening campaign, 3,6-diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitriles, e.g. I, were discovered as a new class of PfGSK-3 inhibitors. Being less active on GSK-3 homologues of other species, the title compds. showed selectivity in favor of PfGSK-3. Taking into account the X-ray structure of a related mol. in complex with human GSK-3 (HsGSK-3), a model was computed for the comparison of inhibitor complexes with the plasmodial and human enzymes. It was found that subtle differences in the ATP-binding pockets are responsible for the obsd. PfGSK-3 vs HsGSK-3 selectivity. Representatives of the title compd. class exhibited micromolar IC50 values against P. falciparum erythrocyte stage parasites. These results suggest that inhibitors of PfGSK-3 could be developed as potential antimalarial drugs.
- 275Alam, M. M.; Sanchez-Azqueta, A.; Janha, O.; Flannery, E. L.; Mahindra, A.; Mapesa, K.; Char, A. B.; Sriranganadane, D.; Brancucci, N. M. B.; Antonova-Koch, Y.; Crouch, K.; Simwela, N. V.; Millar, S. B.; Akinwale, J.; Mitcheson, D.; Solyakov, L.; Dudek, K.; Jones, C.; Zapatero, C.; Doerig, C.; Nwakanma, D. C.; Vazquez, M. J.; Colmenarejo, G.; Lafuente-Monasterio, M. J.; Leon, M. L.; Godoi, P. H. C.; Elkins, J. M.; Waters, A. P.; Jamieson, A. G.; Alvaro, E. F.; Ranford-Cartwright, L. C.; Marti, M.; Winzeler, E. A.; Gamo, F. J.; Tobin, A. B. Validation of the protein kinase PfCLK3 as a multistage cross-species malarial drug target. Science 2019, 365, eaau1682 DOI: 10.1126/science.aau1682
- 276Chapman, T. M.; Osborne, S. A.; Wallace, C.; Birchall, K.; Bouloc, N.; Jones, H. M.; Ansell, K. H.; Taylor, D. L.; Clough, B.; Green, J. L.; Holder, A. A. Optimization of an imidazopyridazine series of inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1). J. Med. Chem. 2014, 57, 3570– 3587, DOI: 10.1021/jm500342d[ACS Full Text], [CAS], Google Scholar276https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXltF2rtLs%253D&md5=4aa3206475bb43f750477da00f9a66b6Optimization of an Imidazopyridazine Series of Inhibitors of Plasmodium falciparum Calcium-Dependent Protein Kinase 1 (PfCDPK1)Chapman, Timothy M.; Osborne, Simon A.; Wallace, Claire; Birchall, Kristian; Bouloc, Nathalie; Jones, Hayley M.; Ansell, Keith H.; Taylor, Debra L.; Clough, Barbara; Green, Judith L.; Holder, Anthony A.Journal of Medicinal Chemistry (2014), 57 (8), 3570-3587CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A structure-guided design approach using a homol. model of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1) was used to improve the potency of a series of imidazopyridazine inhibitors as potential antimalarial agents. This resulted in high affinity compds. with PfCDPK1 enzyme IC50 values less than 10 nM and in vitroP. falciparum antiparasite EC50 values down to 12 nM, although these compds. did not have suitable ADME properties to show in vivo efficacy in a mouse model. Structural modifications designed to address the ADME issues, in particular permeability, were initially accompanied by losses in antiparasite potency, but further optimization allowed a good balance in the compd. profile to be achieved. Upon testing in vivo in a murine model of efficacy against malaria, high levels of compd. exposure relative to their in vitro activities were achieved, and the modest efficacy that resulted raises questions about the level of effect that is achievable through the targeting of PfCDPK1.
- 277Ojo, K. K.; Eastman, R. T.; Vidadala, R.; Zhang, Z.; Rivas, K. L.; Choi, R.; Lutz, J. D.; Reid, M. C.; Fox, A. M.; Hulverson, M. A.; Kennedy, M.; Isoherranen, N.; Kim, L. M.; Comess, K. M.; Kempf, D. J.; Verlinde, C. L.; Su, X. Z.; Kappe, S. H.; Maly, D. J.; Fan, E.; Van Voorhis, W. C. A specific inhibitor of PfCDPK4 blocks malaria transmission: chemical-genetic validation. J. Infect. Dis. 2014, 209, 275– 284, DOI: 10.1093/infdis/jit522[Crossref], [PubMed], [CAS], Google Scholar277https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXit1Smtg%253D%253D&md5=cc5499eca2d177bfa8cb1c523eb54525A Specific Inhibitor of PfCDPK4 Blocks Malaria Transmission: Chemical-genetic ValidationOjo, Kayode K.; Eastman, Richard T.; Vidadala, Rama Subba Rao; Zhang, Zhongsheng; Rivas, Kasey L.; Choi, Ryan; Lutz, Justin D.; Reid, Molly C.; Fox, Anna M. W.; Hulverson, Matthew A.; Kennedy, Mark; Isoherranen, Nina; Kim, Laura M.; Comess, Kenneth M.; Kempf, Dale J.; Verlinde, Christophe L. M. J.; Su, Xin-zhuan; Kappe, Stefan H. I.; Maly, Dustin J.; Fan, Erkang; Van Voorhis, Wesley C.Journal of Infectious Diseases (2014), 209 (2), 275-284CODEN: JIDIAQ; ISSN:0022-1899. (Oxford University Press)Malaria parasites are transmitted by mosquitoes, and blocking parasite transmission is crit. in reducing or eliminating malaria in endemic regions. Here, we report the pharmacol. characterization of a new class of malaria transmission-blocking compds. that acts via the inhibition of Plasmodia CDPK4 enzyme. We demonstrate that these compds. achieved selectivity over mammalian kinases by capitalizing on a small serine gatekeeper residue in the active site of the Plasmodium CDPK4 enzyme. To directly confirm the mechanism of action of these compds., we generated P. falciparum parasites that express a drug-resistant methionine gatekeeper (S147M) CDPK4 mutant. Mutant parasites showed a shift in exflagellation EC50 relative to the wild-type strains in the presence of compd. 1294, providing chem.-genetic evidence that CDPK4 is the target of the compd. Pharmacokinetic analyses suggest that coformulation of this transmission-blocking agent with asexual stage antimalarials such as artemisinin combination therapy (ACT) is a promising option for drug delivery that may reduce transmission of malaria including drug-resistant strains. Ongoing studies include refining the compds. to improve efficacy and toxicol. properties for efficient blocking of malaria transmission.
- 278Baker, D. A.; Stewart, L. B.; Large, J. M.; Bowyer, P. W.; Ansell, K. H.; Jimenez-Diaz, M. B.; El Bakkouri, M.; Birchall, K.; Dechering, K. J.; Bouloc, N. S.; Coombs, P. J.; Whalley, D.; Harding, D. J.; Smiljanic-Hurley, E.; Wheldon, M. C.; Walker, E. M.; Dessens, J. T.; Lafuente, M. J.; Sanz, L. M.; Gamo, F. J.; Ferrer, S. B.; Hui, R.; Bousema, T.; Angulo-Barturen, I.; Merritt, A. T.; Croft, S. L.; Gutteridge, W. E.; Kettleborough, C. A.; Osborne, S. A. A potent series targeting the malarial cGMP-dependent protein kinase clears infection and blocks transmission. Nat. Commun. 2017, 8, 430, DOI: 10.1038/s41467-017-00572-x[Crossref], [PubMed], [CAS], Google Scholar278https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cbkvF2rtg%253D%253D&md5=3b6f60a0c537ab7295a82f8a8f551ff4A potent series targeting the malarial cGMP-dependent protein kinase clears infection and blocks transmissionBaker David A; Stewart Lindsay B; Bowyer Paul W; Walker Eloise M; Dessens Johannes T; Croft Simon L; Gutteridge Winston E; Large Jonathan M; Ansell Keith H; Birchall Kristian; Bouloc Nathalie S; Coombs Peter J; Whalley David; Harding Denise J; Smiljanic-Hurley Ela; Wheldon Mary C; Merritt Andy T; Kettleborough Catherine A; Osborne Simon A; Jimenez-Diaz Maria B; Lafuente Maria Jose; Sanz Laura M; Gamo Francisco-Javier; Ferrer Santiago B; Angulo-Barturen Inigo; El Bakkouri Majida; Hui Raymond; El Bakkouri Majida; Hui Raymond; Dechering Koen J; Bousema TeunNature communications (2017), 8 (1), 430 ISSN:.To combat drug resistance, new chemical entities are urgently required for use in next generation anti-malarial combinations. We report here the results of a medicinal chemistry programme focused on an imidazopyridine series targeting the Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG). The most potent compound (ML10) has an IC50 of 160 pM in a PfPKG kinase assay and inhibits P. falciparum blood stage proliferation in vitro with an EC50 of 2.1 nM. Oral dosing renders blood stage parasitaemia undetectable in vivo using a P. falciparum SCID mouse model. The series targets both merozoite egress and erythrocyte invasion, but crucially, also blocks transmission of mature P. falciparum gametocytes to Anopheles stephensi mosquitoes. A co-crystal structure of PvPKG bound to ML10, reveals intimate molecular contacts that explain the high levels of potency and selectivity we have measured. The properties of this series warrant consideration for further development to produce an antimalarial drug.Protein kinases are promising drug targets for treatment of malaria. Here, starting with a medicinal chemistry approach, Baker et al. generate an imidazopyridine that selectively targets Plasmodium falciparum PKG, inhibits blood stage parasite growth in vitro and in mice and blocks transmission to mosquitoes.
- 279Milne, G.; Webster, J. P.; Walker, M. Toxoplasma gondii: an underestimated threat?. Trends Parasitol. 2020, 36, 959, DOI: 10.1016/j.pt.2020.08.005[Crossref], [PubMed], [CAS], Google Scholar279https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3s%252FntFSnsA%253D%253D&md5=5d22c9a0b770752d1ac9126a0909ca6dToxoplasma gondii: AnUnderestimated Threat?Milne Gregory; Webster Joanne P; Walker MartinTrends in parasitology (2020), 36 (12), 959-969 ISSN:.Traditionally, the protozoan parasite Toxoplasma gondii has been thought of as relevant to public health primarily within the context of congenital toxoplasmosis or postnatally acquired disease in immunocompromised patients. However, latent T.gondii infection has been increasingly associated with a wide variety of neuropsychiatric disorders and, more recently, causal frameworks for these epidemiological associations have been proposed. We present assimilated evidence on the associations between T.gondii and various human neuropsychiatric disorders and outline how these may be explained within a unifying causal framework. We argue that the occult effects of latent T.gondii infection likely outweigh the recognised overt morbidity caused by toxoplasmosis, substantially raising the public health importance of this parasite.
- 280Lourido, S.; Shuman, J.; Zhang, C.; Shokat, K. M.; Hui, R.; Sibley, L. D. Calcium-dependent protein kinase 1 is an essential regulator of exocytosis in Toxoplasma. Nature 2010, 465, 359– 362, DOI: 10.1038/nature09022[Crossref], [PubMed], [CAS], Google Scholar280https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmt1Oisr0%253D&md5=750f6bf5c933759605574d4a2ab5acccCalcium-dependent protein kinase 1 is an essential regulator of exocytosis in ToxoplasmaLourido, Sebastian; Shuman, Joel; Zhang, Chao; Shokat, Kevan M.; Hui, Raymond; Sibley, L. DavidNature (London, United Kingdom) (2010), 465 (7296), 359-362CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Calcium-regulated exocytosis is a ubiquitous process in eukaryotes, whereby secretory vesicles fuse with the plasma membrane and release their contents in response to an intracellular calcium surge. This process regulates various cellular functions such as plasma membrane repair in plants and animals, the discharge of defensive spikes in Paramecium, and the secretion of insulin from pancreatic cells, immune modulators from lymphocytes, and chem. transmitters from neurons. In animal cells, serine/threonine kinases including cAMP-dependent protein kinase, protein kinase C and calmodulin kinases have been implicated in calcium-signal transduction leading to regulated secretion. Although plants and protozoa also regulate secretion by means of intracellular calcium, the method by which these signals are relayed has not been explained. Here we show that the Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) is an essential regulator of calcium-dependent exocytosis in this opportunistic human pathogen. Conditional suppression of TgCDPK1 revealed that it controls calcium-dependent secretion of specialized organelles called micronemes, resulting in a block of essential phenotypes including parasite motility, host-cell invasion, and egress. These phenotypes were recapitulated by using a chem. biol. approach in which pyrazolopyrimidine-derived compds. specifically inhibited TgCDPK1 and disrupted the parasite's life cycle at stages dependent on microneme secretion. Inhibition was specific to TgCDPK1, because expression of a resistant mutant kinase reversed sensitivity to the inhibitor. TgCDPK1 is conserved among apicomplexans and belongs to a family of kinases shared with plants and ciliates, suggesting that related CDPKs may have a function in calcium-regulated secretion in other organisms. Because this kinase family is absent from mammalian hosts, it represents a validated target that may be exploitable for chemotherapy against T. gondii and related apicomplexans.
- 281Hui, R.; El Bakkouri, M.; Sibley, L. D. Designing selective inhibitors for calcium-dependent protein kinases in apicomplexans. Trends Pharmacol. Sci. 2015, 36, 452– 460, DOI: 10.1016/j.tips.2015.04.011[Crossref], [PubMed], [CAS], Google Scholar281https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXotVWitLk%253D&md5=0081edfce5d381c6a34c396b011c24b8Designing selective inhibitors for calcium-dependent protein kinases in apicomplexansHui, Raymond; El Bakkouri, Majida; Sibley, L. DavidTrends in Pharmacological Sciences (2015), 36 (7), 452-460CODEN: TPHSDY; ISSN:0165-6147. (Elsevier Ltd.)A review. Apicomplexan parasites cause some of the most severe human diseases, including malaria (caused by Plasmodium), toxoplasmosis, and cryptosporidiosis. Treatments are limited by the lack of effective drugs and development of resistance to available agents. By exploiting novel features of protein kinases in these parasites, it may be possible to develop new treatments. We summarize here recent advances in identifying small mol. inhibitors against a novel family of plant-like, calcium-dependent kinases that are uniquely expanded in apicomplexan parasites. Anal. of the 3D structure, activation mechanism, and sensitivity to small mols. had identified several attractive chem. scaffolds that are potent and selective inhibitors of these parasite kinases. Further optimization of these leads may yield promising new drugs for treatment of these parasitic infections.
- 282Johnson, S. M.; Murphy, R. C.; Geiger, J. A.; DeRocher, A. E.; Zhang, Z.; Ojo, K. K.; Larson, E. T.; Perera, B. G.; Dale, E. J.; He, P.; Reid, M. C.; Fox, A. M.; Mueller, N. R.; Merritt, E. A.; Fan, E.; Parsons, M.; Van Voorhis, W. C.; Maly, D. J. Development of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) inhibitors with potent anti-toxoplasma activity. J. Med. Chem. 2012, 55, 2416– 2426, DOI: 10.1021/jm201713h[ACS Full Text], [CAS], Google Scholar282https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XitVeksb8%253D&md5=862ac0e5066f60d7eeaccc723c2c4e75Development of Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitors with Potent Anti-Toxoplasma ActivityJohnson, Steven M.; Murphy, Ryan C.; Geiger, Jennifer A.; DeRocher, Amy E.; Zhang, Zhongsheng; Ojo, Kayode K.; Larson, Eric T.; Perera, B. Gayani K.; Dale, Edward J.; He, Panqing; Reid, Molly C.; Fox, Anna M. W.; Mueller, Natascha R.; Merritt, Ethan A.; Fan, Erkang; Parsons, Marilyn; Van Voorhis, Wesley C.; Maly, Dustin J.Journal of Medicinal Chemistry (2012), 55 (5), 2416-2426CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Toxoplasmosis is a disease of prominent health concern that is caused by the protozoan parasite Toxoplasma gondii. Proliferation of T. gondii is dependent on its ability to invade host cells, which is mediated in part by calcium-dependent protein kinase 1 (CDPK1). We have developed ATP competitive inhibitors of TgCDPK1 that block invasion of parasites into host cells, preventing their proliferation. The presence of a unique glycine gatekeeper residue in TgCDPK1 permits selective inhibition of the parasite enzyme over human kinases. These potent TgCDPK1 inhibitors do not inhibit the growth of human cell lines and represent promising candidates as toxoplasmosis therapeutics.
- 283Lourido, S.; Zhang, C.; Lopez, M. S.; Tang, K.; Barks, J.; Wang, Q.; Wildman, S. A.; Shokat, K. M.; Sibley, L. D. Optimizing small molecule inhibitors of calcium-dependent protein kinase 1 to prevent infection by Toxoplasma gondii. J. Med. Chem. 2013, 56, 3068– 3077, DOI: 10.1021/jm4001314[ACS Full Text], [CAS], Google Scholar283https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjslSgt78%253D&md5=352bb9e5b5304656aab52da763202b68Optimizing Small Molecule Inhibitors of Calcium-Dependent Protein Kinase 1 to Prevent Infection by Toxoplasma gondiiLourido, Sebastian; Zhang, Chao; Lopez, Michael S.; Tang, Keliang; Barks, Jennifer; Wang, Qiuling; Wildman, Scott A.; Shokat, Kevan M.; Sibley, L. DavidJournal of Medicinal Chemistry (2013), 56 (7), 3068-3077CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Toxoplasma gondii is sensitive to bulky pyrazolo [3,4-d] pyrimidine (PP) inhibitors due to the presence of a Gly gatekeeper in the essential calcium dependent protein kinase 1 (CDPK1). Here we synthesized a no. of new derivs. of 3-methyl-benzyl-PP (3-MB-PP, or 1). The potency of PP analogs in inhibiting CDPK1 enzyme activity in vitro (low nM IC50 values) and blocking parasite growth in host cell monolayers in vivo (low μM EC50 values) were highly correlated and occurred in a CDPK1-specific manner. Chem. modification of the PP scaffold to increase half-life in the presence of microsomes in vitro led to identification of compds. with enhanced stability while retaining activity. Several of these more potent compds. were able to prevent lethal infection with T. gondii in the mouse model. Collectively, the strategies outlined here provide a route for development of more effective compds. for treatment of toxoplasmosis and perhaps related parasitic diseases.
- 284Vidadala, R. S.; Rivas, K. L.; Ojo, K. K.; Hulverson, M. A.; Zambriski, J. A.; Bruzual, I.; Schultz, T. L.; Huang, W.; Zhang, Z.; Scheele, S.; DeRocher, A. E.; Choi, R.; Barrett, L. K.; Siddaramaiah, L. K.; Hol, W. G.; Fan, E.; Merritt, E. A.; Parsons, M.; Freiberg, G.; Marsh, K.; Kempf, D. J.; Carruthers, V. B.; Isoherranen, N.; Doggett, J. S.; Van Voorhis, W. C.; Maly, D. J. Development of an orally available and central nervous system (CNS) penetrant Toxoplasma gondii Calcium-dependent protein kinase 1 (TgCDPK1) inhibitor with minimal human ether-a-go-go-related gene (hERG) activity for the treatment of Toxoplasmosis. J. Med. Chem. 2016, 59, 6531– 6546, DOI: 10.1021/acs.jmedchem.6b00760[ACS Full Text], [CAS], Google Scholar284https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVSrsr%252FM&md5=8eb12f3703985ad69b921f1495858081Development of an Orally Available and Central Nervous System (CNS) Penetrant Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related Gene (hERG) Activity for the Treatment of ToxoplasmosisVidadala, Rama Subba Rao; Rivas, Kasey L.; Ojo, Kayode K.; Hulverson, Matthew A.; Zambriski, Jennifer A.; Bruzual, Igor; Schultz, Tracey L.; Huang, Wenlin; Zhang, Zhongsheng; Scheele, Suzanne; DeRocher, Amy E.; Choi, Ryan; Barrett, Lynn K.; Siddaramaiah, Latha Kallur; Hol, Wim G. J.; Fan, Erkang; Merritt, Ethan A.; Parsons, Marilyn; Freiberg, Gail; Marsh, Kennan; Kempf, Dale J.; Carruthers, Vern B.; Isoherranen, Nina; Doggett, J. Stone; Van Voorhis, Wesley C.; Maly, Dustin J.Journal of Medicinal Chemistry (2016), 59 (13), 6531-6546CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)New therapies are needed for the treatment of toxoplasmosis, which is a disease caused by the protozoan parasite Toxoplasma gondii. To this end, we previously developed a potent and selective inhibitor (compd. 1) of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) that possesses antitoxoplasmosis activity in vitro and in vivo. Unfortunately, 1 has potent human ether-a-go-go-related gene (hERG) inhibitory activity, assocd. with long Q-T syndrome, and consequently presents a cardiotoxicity risk. Here, we describe the identification of an optimized TgCDPK1 inhibitor 32, which does not have a hERG liability and possesses a favorable pharmacokinetic profile in small and large animals. 32(I) is CNS-penetrant and highly effective in acute and latent mouse models of T. gondii infection, significantly reducing the amt. of parasite in the brain, spleen, and peritoneal fluid and reducing brain cysts by >85%. These properties make 32 a promising lead for the development of a new antitoxoplasmosis therapy.
- 285Rutaganira, F. U.; Barks, J.; Dhason, M. S.; Wang, Q.; Lopez, M. S.; Long, S.; Radke, J. B.; Jones, N. G.; Maddirala, A. R.; Janetka, J. W.; El Bakkouri, M.; Hui, R.; Shokat, K. M.; Sibley, L. D. nhibition of Calcium dependent protein kinase 1 (CDPK1) by pyrazolopyrimidine analogs decreases establishment and reoccurrence of central nervous system disease by Toxoplasma gondii. J. Med. Chem. 2017, 60, 9976– 9989, DOI: 10.1021/acs.jmedchem.7b01192[ACS Full Text], [CAS], Google Scholar285https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFensbzO&md5=27908eedbcadb1132f254fda63336842Inhibition of Calcium Dependent Protein Kinase 1 (CDPK1) by Pyrazolopyrimidine Analogs Decreases Establishment and Reoccurrence of Central Nervous System Disease by Toxoplasma gondiiRutaganira, Florentine U.; Barks, Jennifer; Dhason, Mary Savari; Wang, Qiuling; Lopez, Michael S.; Long, Shaojun; Radke, Joshua B.; Jones, Nathaniel G.; Maddirala, Amarendar R.; Janetka, James W.; El Bakkouri, Majida; Hui, Raymond; Shokat, Kevan M.; Sibley, L. DavidJournal of Medicinal Chemistry (2017), 60 (24), 9976-9989CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Calcium dependent protein kinase 1 (CDPK1) is an essential enzyme in the opportunistic pathogen Toxoplasma gondii. CDPK1 controls multiple processes that are crit. to the intracellular replicative cycle of T. gondii including secretion of adhesins, motility, invasion, and egress. Remarkably, CDPK1 contains a small glycine gatekeeper residue in the ATP binding pocket making it sensitive to ATP-competitive inhibitors with bulky substituents that complement this expanded binding pocket. Here the authors explored structure-activity relationships of a series of pyrazolopyrimidine inhibitors of CDPK1 with the goal of increasing selectivity over host enzymes, improving antiparasite potency, and improving metabolic stability. The resulting lead compd. 24 exhibited excellent enzyme inhibition and selectivity for CDPK1 and potently inhibited parasite growth in vitro. Compd. 24 was also effective at treating acute toxoplasmosis in the mouse, reducing dissemination to the central nervous system, and decreasing reactivation of chronic infection in severely immunocompromised mice. These findings provide proof of concept for the development of small mol. inhibitors of CDPK1 for treatment of CNS toxoplasmosis.
- 286Janetka, J. W.; Hopper, A. T.; Yang, Z.; Barks, J.; Dhason, M. S.; Wang, Q.; Sibley, L. D. Optimizing pyrazolopyrimidine inhibitors of Calcium dependent protein kinase 1 for treatment of acute and chronic toxoplasmosis. J. Med. Chem. 2020, 63, 6144– 6163, DOI: 10.1021/acs.jmedchem.0c00419[ACS Full Text], [CAS], Google Scholar286https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXpsFelsL0%253D&md5=6faff1fe52c7b11a9c51298b73d86f6dOptimizing Pyrazolopyrimidine Inhibitors of Calcium Dependent Protein Kinase 1 for Treatment of Acute and Chronic ToxoplasmosisJanetka, James W.; Hopper, Allen T.; Yang, Ziping; Barks, Jennifer; Dhason, Mary Savari; Wang, Qiuling; Sibley, L. DavidJournal of Medicinal Chemistry (2020), 63 (11), 6144-6163CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Calcium dependent protein kinase 1 (CDPK1) is an essential Ser/Thr kinase that controls invasion and egress by the protozoan parasite Toxoplasma gondii. The Gly gatekeeper of CDPK1 makes it exquisitely sensitive to inhibition by small mol. 1H-Pyrazolo[3,4-d]Pyrimidine-4-amine or (PP) compds. that are bulky ATP mimetics. Here we rationally designed, synthesized, and tested a series of novel PP analogs that were evaluated for inhibition of CDPK1 enzyme activity in vitro and parasite growth in cell culture. Optimal substitution on the PP scaffold included 2-pyridyl ethers directed into the hydrophobic pocket and small carbocyclic rings accessing the ribose-binding pocket. Further optimization of the series led to identification of the lead compd. I that displayed excellent potency, selectivity, safety profile, and efficacy in vivo. The results of these studies provide a foundation for further work to optimize CDPK1 inhibitors for the treatment of acute and chronic toxoplasmosis.
- 287Chen, W. C.; Simanjuntak, Y.; Chu, L. W.; Ping, Y. H.; Lee, Y. L.; Lin, Y. L.; Li, W. S. Benzenesulfonamide derivatives as Calcium/calmodulin-dependent protein kinase inhibitors and antiviral agents against dengue and zika virus infections. J. Med. Chem. 2020, 63, 1313– 1327, DOI: 10.1021/acs.jmedchem.9b01779[ACS Full Text], [CAS], Google Scholar287https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhs1elsbg%253D&md5=4222b9a25616a59243c22bfd57b223e7Benzenesulfonamide Derivatives as Calcium/Calmodulin-Dependent Protein Kinase Inhibitors and Antiviral Agents against Dengue and Zika Virus InfectionsChen, Wei-Chia; Simanjuntak, Yogy; Chu, Li-Wei; Ping, Yueh-Hsin; Lee, Yi-Ling; Lin, Yi-Ling; Li, Wen-ShanJournal of Medicinal Chemistry (2020), 63 (3), 1313-1327CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Emerging and resurging mosquito-borne flaviviruses are an important public health challenge. The increased prevalence of dengue virus (DENV) infection has had a significant socioeconomic impact on epidemic countries. The recent outbreak of Zika virus (ZIKV) has created an international public health emergency because ZIKV infection has been linked to congenital defects and Guillain-Barr´e syndrome. To develop potentially prophylactic antiviral drugs for combating these acute infectious diseases, we have targeted the host calcium/calmodulin-dependent kinase II (CaMKII) for inhibition. By using CaMKII structure-guided inhibitor design, we generated four families of benzenesulfonamide (BSA) derivs. for SAR anal. Among these substances, N-(4-cycloheptyl-4-oxobutyl)-4-methoxy-N-phenylbenzenesulfonamide (9) showed superior properties as a lead CaMKII inhibitor and antiviral agent. BSA 9 inhibited CaMKII activity with an IC50 value of 0.79 μM and displayed EC50 values of 1.52 μM and 1.91 μM against DENV and ZIKV infections of human neuronal BE(2)C cells, resp. Notably, 9 significantly reduced the viremia level and increased animal survival time in mouse-challenge models.
- 288Verdonck, S.; Pu, S. Y.; Sorrell, F. J.; Elkins, J. M.; Froeyen, M.; Gao, L. J.; Prugar, L. I.; Dorosky, D. E.; Brannan, J. M.; Barouch-Bentov, R.; Knapp, S.; Dye, J. M.; Herdewijn, P.; Einav, S.; De Jonghe, S. Synthesis and structure-activity relationships of 3,5-disubstituted-pyrrolo[2,3- b]pyridines as inhibitors of Adaptor-associated kinase 1 with antiviral activity. J. Med. Chem. 2019, 62, 5810– 5831, DOI: 10.1021/acs.jmedchem.9b00136[ACS Full Text], [CAS], Google Scholar288https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtVKgtr7P&md5=bdec475534dbe2ad18d1c377f8b4c67dSynthesis and Structure-Activity Relationships of 3,5-Disubstituted-pyrrolo[2,3-b]pyridines as Inhibitors of Adaptor-Associated Kinase 1 with Antiviral ActivityVerdonck, Sven; Pu, Szu-Yuan; Sorrell, Fiona J.; Elkins, Jon M.; Froeyen, Mathy; Gao, Ling-Jie; Prugar, Laura I.; Dorosky, Danielle E.; Brannan, Jennifer M.; Barouch-Bentov, Rina; Knapp, Stefan; Dye, John M.; Herdewijn, Piet; Einav, Shirit; De Jonghe, StevenJournal of Medicinal Chemistry (2019), 62 (12), 5810-5831CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)There are currently no approved drugs for the treatment of emerging viral infections, such as dengue and Ebola. Adaptor-assocd. kinase 1 (AAK1) is a cellular serine-threonine protein kinase that functions as a key regulator of the clathrin-assocd. host adaptor proteins and regulates the intracellular trafficking of multiple unrelated RNA viruses. Moreover, AAK1 is overexpressed specifically in dengue virus-infected but not bystander cells. Because AAK1 is a promising antiviral drug target, we have embarked on an optimization campaign of a previously identified 7-azaindole analog, yielding novel pyrrolo[2,3-b]pyridines with high AAK1 affinity. The optimized compds. demonstrate improved activity against dengue virus both in vitro and in human primary dendritic cells and the unrelated Ebola virus. These findings demonstrate that targeting cellular AAK1 may represent a promising broad-spectrum antiviral strategy.
- 289Mohedas, A. H.; Wang, Y.; Sanvitale, C. E.; Canning, P.; Choi, S.; Xing, X.; Bullock, A. N.; Cuny, G. D.; Yu, P. B. Structure-activity relationship of 3,5-diaryl-2-aminopyridine ALK2 inhibitors reveals unaltered binding affinity for fibrodysplasia ossificans progressiva causing mutants. J. Med. Chem. 2014, 57, 7900– 7915, DOI: 10.1021/jm501177w[ACS Full Text], [CAS], Google Scholar289https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht12gu7fP&md5=c5efce9b3d06bbb126aa8a197d3d2b40Structure-Activity Relationship of 3,5-Diaryl-2-aminopyridine ALK2 Inhibitors Reveals Unaltered Binding Affinity for Fibrodysplasia Ossificans Progressiva Causing MutantsMohedas, Agustin H.; Wang, You; Sanvitale, Caroline E.; Canning, Peter; Choi, Sungwoon; Xing, Xuechao; Bullock, Alex N.; Cuny, Gregory D.; Yu, Paul B.Journal of Medicinal Chemistry (2014), 57 (19), 7900-7915CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)There are currently no effective therapies for fibrodysplasia ossificans progressiva (FOP), a debilitating and progressive heterotopic ossification disease caused by activating mutations of ACVR1 encoding the BMP type I receptor kinase ALK2. Recently, a subset of these same mutations of ACVR1 have been identified in diffuse intrinsic pontine glioma (DIPG) tumors. Here the authors describe the structure-activity relationship for a series of novel ALK2 inhibitors based on the 2-aminopyridine compd. K02288. Several modifications increased potency in kinase, thermal shift, or cell-based assays of BMP signaling and transcription, as well as selectivity for ALK2 vs. closely related BMP and TGF-β type I receptor kinases. Compds. in this series exhibited a wide range of in vitro cytotoxicity that was not correlated with potency or selectivity, suggesting mechanisms independent of BMP or TGF-β inhibition. The study also highlights a potent 2-methylpyridine deriv. I (LDN-214117) with a high degree of selectivity for ALK2 and low cytotoxicity that could provide a template for preclin. development. Contrary to the notion that activating mutations of ALK2 might alter inhibitor efficacy due to potential conformational changes in the ATP-binding site, the compds. demonstrated consistent binding to a panel of mutant and wild-type ALK2 proteins. Thus, BMP inhibitors identified via activity against wild-type ALK2 signaling are likely to be of clin. relevance for the diverse ALK2 mutant proteins assocd. with FOP and DIPG.
- 290Fushimi, M.; Fujimori, I.; Wakabayashi, T.; Hasui, T.; Kawakita, Y.; Imamura, K.; Kato, T.; Murakami, M.; Ishii, T.; Kikko, Y.; Kasahara, M.; Nakatani, A.; Hiura, Y.; Miyamoto, M.; Saikatendu, K.; Zou, H.; Lane, S. W.; Lawson, J. D.; Imoto, H. Discovery of potent, selective, and brain-penetrant 1 H-pyrazol-5-yl-1 H-pyrrolo[2,3- b]pyridines as Anaplastic lymphoma kinase (ALK) inhibitors. J. Med. Chem. 2019, 62, 4915– 4935, DOI: 10.1021/acs.jmedchem.8b01630[ACS Full Text], [CAS], Google Scholar290https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXnvFCgsrg%253D&md5=8d3bac7f718930a6102cb7855af501cbDiscovery of potent, selective, and brain-penetrant 1H-pyrazol-5-yl-1H-pyrrolo[2,3-b]pyridines as anaplastic lymphoma kinase (ALK) inhibitorsFushimi, Makoto; Fujimori, Ikuo; Wakabayashi, Takeshi; Hasui, Tomoaki; Kawakita, Youichi; Imamura, Keisuke; Kato, Tomoko; Murakami, Morio; Ishii, Tsuyoshi; Kikko, Yorifumi; Kasahara, Maki; Nakatani, Atsushi; Hiura, Yuto; Miyamoto, Maki; Saikatendu, Kumar; Zou, Hua; Lane, Scott Weston; Lawson, J. David; Imoto, HiroshiJournal of Medicinal Chemistry (2019), 62 (10), 4915-4935CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Anaplastic lymphoma kinase (ALK), a member of the receptor tyrosine kinase family, is predominantly expressed in the brain and implicated in neuronal development and cognition. However, the detailed function of ALK in the central nervous system (CNS) is still unclear. To elucidate the role of ALK in the CNS, it was necessary to discover a potent, selective, and brain-penetrant ALK inhibitor. Scaffold hopping and lead optimization of N-(2,4-difluorobenzyl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-amine 1 guided by a cocrystal structure of compd. 1 bound to ALK resulted in the identification of (6-(1-(5-fluoropyridin-2-yl)ethoxy)-1-(5-methyl-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)((2S)-2-methylmorpholin-4-yl)methanone 13 as a highly potent, selective, and brain-penetrable compd. I.p. administration of compd. 13 significantly decreased the phosphorylated-ALK (p-ALK) levels in the hippocampus and prefrontal cortex in the mouse brain. These results suggest that compd. 13 could serve as a useful chem. probe to elucidate the mechanism of ALK-mediated brain functions and the therapeutic potential of ALK inhibition.
- 291Bung, N.; Surepalli, S.; Seshadri, S.; Patel, S.; Peddasomayajula, S.; Kummari, L. K.; Kumar, S. T.; Babu, P. P.; Parsa, K. V. L.; Poondra, R. R.; Bulusu, G.; Misra, P. 2-[2-(4-(trifluoromethyl)phenylamino)thiazol-4-yl]acetic acid (Activator-3) is a potent activator of AMPK. Sci. Rep. 2018, 8, 9599, DOI: 10.1038/s41598-018-27974-1[Crossref], [PubMed], [CAS], Google Scholar291https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3c%252FhslChtA%253D%253D&md5=221665dc3822f9b7f7b40a1ed559524c2-[2-(4-(trifluoromethyl)phenylamino)thiazol-4-yl]acetic acid (Activator-3) is a potent activator of AMPKBung Navneet; Bulusu Gopalakrishnan; Surepalli Sobhitha; Peddasomayajula Saranya; Kummari Lalith Kumar; Parsa Kishore V L; Poondra Rajamohan Reddy; Bulusu Gopalakrishnan; Misra Parimal; Seshadri Sriram; Patel Sweta; Kummari Lalith Kumar; Kummari Lalith Kumar; Kumar Sireesh T; Babu Phanithi PrakashScientific reports (2018), 8 (1), 9599 ISSN:.AMPK is considered as a potential high value target for metabolic disorders. Here, we present the molecular modeling, in vitro and in vivo characterization of Activator-3, 2-[2-(4-(trifluoromethyl)phenylamino)thiazol-4-yl]acetic acid, an AMP mimetic and a potent pan-AMPK activator. Activator-3 and AMP likely share common activation mode for AMPK activation. Activator-3 enhanced AMPK phosphorylation by upstream kinase LKB1 and protected AMPK complex against dephosphorylation by PP2C. Molecular modeling analyses followed by in vitro mutant AMPK enzyme assays demonstrate that Activator-3 interacts with R70 and R152 of the CBS1 domain on AMPK γ subunit near AMP binding site. Activator-3 and C2, a recently described AMPK mimetic, bind differently in the γ subunit of AMPK. Activator-3 unlike C2 does not show cooperativity of AMPK activity in the presence of physiological concentration of ATP (2 mM). Activator-3 displays good pharmacokinetic profile in rat blood plasma with minimal brain penetration property. Oral treatment of High Sucrose Diet (HSD) fed diabetic rats with 10 mg/kg dose of Activator-3 once in a day for 30 days significantly enhanced glucose utilization, improved lipid profiles and reduced body weight, demonstrating that Activator-3 is a potent AMPK activator that can alleviate the negative metabolic impact of high sucrose diet in rat model.
- 292Lee, T. W.; Verhey, T. B.; Antiperovitch, P. A.; Atamanyuk, D.; Desroy, N.; Oliveira, C.; Denis, A.; Gerusz, V.; Drocourt, E.; Loutet, S. A.; Hamad, M. A.; Stanetty, C.; Andres, S. N.; Sugiman-Marangos, S.; Kosma, P.; Valvano, M. A.; Moreau, F.; Junop, M. S. Structural-functional studies of Burkholderia cenocepacia D-glycero-β-D-manno-heptose 7-phosphate kinase (HldA) and characterization of inhibitors with antibiotic adjuvant and antivirulence properties. J. Med. Chem. 2013, 56, 1405– 1417, DOI: 10.1021/jm301483h[ACS Full Text], [CAS], Google Scholar292https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVyiurrI&md5=288f3ec86757f6d49c86f8dad3927223Structural-Functional Studies of Burkholderia cenocepacia D-Glycero-β-D-manno-heptose 7-Phosphate Kinase (HldA) and Characterization of Inhibitors with Antibiotic Adjuvant and Antivirulence PropertiesLee, Ting-Wai; Verhey, Theodore B.; Antiperovitch, Pavel A.; Atamanyuk, Dmytro; Desroy, Nicolas; Oliveira, Chrystelle; Denis, Alexis; Gerusz, Vincent; Drocourt, Elodie; Loutet, Slade A.; Hamad, Mohamad A.; Stanetty, Christian; Andres, Sara N.; Sugiman-Marangos, Seiji; Kosma, Paul; Valvano, Miguel A.; Moreau, Francois; Junop, Murray S.Journal of Medicinal Chemistry (2013), 56 (4), 1405-1417CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)As an essential constituent of the outer membrane of Gram-neg. bacteria, lipopolysaccharide contributes significantly to virulence and antibiotic resistance. The lipopolysaccharide biosynthetic pathway therefore serves as a promising therapeutic target for antivirulence drugs and antibiotic adjuvants. Here we report the structural-functional studies of D-glycero-β-D-manno-heptose 7-phosphate kinase (HldA), an absolutely conserved enzyme in this pathway, from Burkholderia cenocepacia. HldA is structurally similar to members of the PfkB carbohydrate kinase family and appears to catalyze heptose phosphorylation via an in-line mechanism mediated mainly by a conserved aspartate, Asp270. Moreover, we report the structures of HldA in complex with two potent inhibitors in which both inhibitors adopt a folded conformation and occupy the nucleotide-binding sites. Together, these results provide important insight into the mechanism of HldA-catalyzed heptose phosphorylation and necessary information for further development of HldA inhibitors.
- 293Mente, S.; Arnold, E.; Butler, T.; Chakrapani, S.; Chandrasekaran, R.; Cherry, K.; DiRico, K.; Doran, A.; Fisher, K.; Galatsis, P.; Green, M.; Hayward, M.; Humphrey, J.; Knafels, J.; Li, J.; Liu, S.; Marconi, M.; McDonald, S.; Ohren, J.; Paradis, V.; Sneed, B.; Walton, K.; Wager, T. Ligand-protein interactions of selective casein kinase 1δ inhibitors. J. Med. Chem. 2013, 56, 6819– 6828, DOI: 10.1021/jm4006324[ACS Full Text], [CAS], Google Scholar293https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1Wlt7jE&md5=bdc600c0977cc4f0f4de40882e1c17b5Ligand-Protein Interactions of Selective Casein Kinase 1δ InhibitorsMente, Scot; Arnold, Eric; Butler, Todd; Chakrapani, Subramanyam; Chandrasekaran, Ramalakshmi; Cherry, Kevin; DiRico, Ken; Doran, Angela; Fisher, Katherine; Galatsis, Paul; Green, Michael; Hayward, Matthew; Humphrey, John; Knafels, John; Li, Jianke; Liu, Shenping; Marconi, Michael; McDonald, Scott; Ohren, Jeff; Paradis, Vanessa; Sneed, Blossom; Walton, Kevin; Wager, TravisJournal of Medicinal Chemistry (2013), 56 (17), 6819-6828CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Casein kinase 1δ (CK1δ) and 1ε (CK1ε) are believed to be necessary enzymes for the regulation of circadian rhythms in all mammals. On the basis of the authors' previously published work demonstrating a CK1ε-preferring compd. to be an ineffective circadian clock modulator, the authors have synthesized a series of pyrazole-substituted pyridine inhibitors, selective for the CK1δ isoform. Addnl., using structure-based drug design, the authors have been able to exploit differences in the hinge region between CK1δ and p38 to find selective inhibitors that have minimal p38 activity. The SAR, brain exposure, and the effect of these inhibitors on mouse circadian rhythms are described. The in vivo evaluation of these inhibitors demonstrates that selective inhibition of CK1δ at sufficient central exposure levels is capable of modulating circadian rhythms.
- 294Lee, J. W.; Hirota, T.; Ono, D.; Honma, S.; Honma, K. I.; Park, K.; Kay, S. A. Chemical control of mammalian circadian behavior through dual inhibition of Casein kinase iα and δ. J. Med. Chem. 2019, 62, 1989– 1998, DOI: 10.1021/acs.jmedchem.8b01541[ACS Full Text], [CAS], Google Scholar294https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisVWjsr0%253D&md5=e7348872080ba7a8f8dc7c25c82b640eChemical control of mammalian circadian behavior through dual inhibition of casein kinase Iα and δLee, Jae Wook; Hirota, Tsuyoshi; Ono, Daisuke; Honma, Sato; Honma, Ken-ichi; Park, Keunwan; Kay, Steve A.Journal of Medicinal Chemistry (2019), 62 (4), 1989-1998CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Circadian rhythms are controlled by transcriptional feedback loops of clock genes and proteins. The stability of clock proteins is regulated by post-translational modification, such as phosphorylation by kinases. In particular, casein kinase I (CKI) phosphorylates the PER protein to regulate proteasomal degrdn. and nuclear localization. Therefore, CKI inhibition can modulate mammalian circadian rhythms. In the present study, we have developed novel CKIα and CKIδ dual inhibitors by extensive structural modification of N9 and C2 position of longdaysin. We identified NCC007 (I) that showed stronger period effects (0.32 μM for 5 h period lengthening) in a cell-based circadian assay. The following in vitro kinase assay showed that I inhibited CKIα and CKIδ with an IC50 of 1.8 and 3.6 μM. We further demonstrated that I lengthened the period of mouse behavioral rhythms in vivo. Thus, I is a valuable tool compd. to control circadian rhythms through CKI inhibition.
- 295Salado, I. G.; Redondo, M.; Bello, M. L.; Perez, C.; Liachko, N. F.; Kraemer, B. C.; Miguel, L.; Lecourtois, M.; Gil, C.; Martinez, A.; Perez, D. I. Protein kinase CK-1 inhibitors as new potential drugs for amyotrophic lateral sclerosis. J. Med. Chem. 2014, 57, 2755– 2772, DOI: 10.1021/jm500065f[ACS Full Text], [CAS], Google Scholar295https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXjsVehsLc%253D&md5=52aad257a2054c93a8fcbafab7a8cb3dProtein Kinase CK-1 Inhibitors As New Potential Drugs for Amyotrophic Lateral SclerosisSalado, Irene G.; Redondo, Miriam; Bello, Murilo L.; Perez, Concepcion; Liachko, Nicole F.; Kraemer, Brian C.; Miguel, Laetitia; Lecourtois, Magalie; Gil, Carmen; Martinez, Ana; Perez, Daniel I.Journal of Medicinal Chemistry (2014), 57 (6), 2755-2772CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease where motor neurons in cortex, brain stem, and spinal cord die progressively, resulting in muscle wasting, paralysis, and death. Currently, effective therapies for ALS are lacking; however, identification of pathol. TAR DNA-binding protein 43 (TDP-43) as the hallmark lesion in sporadic ALS suggests new therapeutic targets for pharmacol. intervention. Pathol. TDP-43 phosphorylation appears to drive the onset and progression of ALS and may result from upregulation of the protein kinase CK-1 in affected neurons, resulting in postranslational TDP-43 modification. Consequently, brain penetrant specific CK-1 inhibitors may provide a new therapeutic strategy for treating ALS and other TDP-43 proteinopathies. Using a chem. genetic approach, we report the discovery and further optimization of a no. of potent CK-1δ inhibitors. Moreover, these small heterocyclic mols. are able to prevent TDP-43 phosphorylation in cell cultures, to increase Drosophila lifespan by redn. of TDP-43 neurotoxicity, and are predicted to cross the blood-brain barrier. Thus, N-(benzothiazolyl)-2-phenyl-acetamides are valuable drug candidates for further studies and may be a new therapeutic approach for ALS and others pathologies in which TDP-43 is involved.
- 296Kovackova, S.; Chang, L.; Bekerman, E.; Neveu, G.; Barouch-Bentov, R.; Chaikuad, A.; Heroven, C.; Sala, M.; De Jonghe, S.; Knapp, S.; Einav, S.; Herdewijn, P. Selective inhibitors of cyclin G associated kinase (GAK) as anti-hepatitis C agents. J. Med. Chem. 2015, 58, 3393– 3410, DOI: 10.1021/jm501759m[ACS Full Text], [CAS], Google Scholar296https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXlsFGntLY%253D&md5=ed7f93eb3d49f6c7265dd2c0da880b43Selective Inhibitors of Cyclin G Associated Kinase (GAK) as Anti-Hepatitis C AgentsKovackova, Sona; Chang, Lei; Bekerman, Elena; Neveu, Gregory; Barouch-Bentov, Rina; Chaikuad, Apirat; Heroven, Christina; Sala, Michal; De Jonghe, Steven; Knapp, Stefan; Einav, Shirit; Herdewijn, PietJournal of Medicinal Chemistry (2015), 58 (8), 3393-3410CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Cyclin G assocd. kinase (GAK) emerged as a promising drug target for the treatment of viral infections. However, no potent and selective GAK inhibitors have been reported in the literature to date. This paper describes the discovery of isothiazolo[5,4-b]pyridines as selective GAK inhibitors, with the most potent congeners displaying low nanomolar binding affinity for GAK. Cocrystn. expts. revealed that these compds. behaved as classic type I ATP-competitive kinase inhibitors. In addn., the authors have demonstrated that these compds. exhibit a potent activity against hepatitis C virus (HCV) by inhibiting two temporally distinct steps in the HCV life cycle (i.e., viral entry and assembly). Hence, these GAK inhibitors represent chem. probes to study GAK function in different disease areas where GAK has been implicated (including viral infection, cancer, and Parkinson's disease).
- 297Pu, S. Y.; Wouters, R.; Schor, S.; Rozenski, J.; Barouch-Bentov, R.; Prugar, L. I.; O’Brien, C. M.; Brannan, J. M.; Dye, J. M.; Herdewijn, P.; De Jonghe, S.; Einav, S. Optimization of isothiazolo[4,3- b]pyridine-based inhibitors of cyclin G associated kinase (GAK) with broad-spectrum antiviral activity. J. Med. Chem. 2018, 61, 6178– 6192, DOI: 10.1021/acs.jmedchem.8b00613[ACS Full Text], [CAS], Google Scholar297https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXht1altLfP&md5=fe33e256835ea01c5e1932c3ccea7eacOptimization of Isothiazolo[4,3-b]pyridine-Based Inhibitors of Cyclin G Associated Kinase (GAK) with Broad-Spectrum Antiviral ActivityPu, Szu-Yuan; Wouters, Randy; Schor, Stanford; Rozenski, Jef; Barouch-Bentov, Rina; Prugar, Laura I.; O'Brien, Cecilia M.; Brannan, Jennifer M.; Dye, John M.; Herdewijn, Piet; De Jonghe, Steven; Einav, ShiritJournal of Medicinal Chemistry (2018), 61 (14), 6178-6192CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)There is an urgent need for strategies to combat dengue and other emerging viral infections. We reported that cyclin G-assocd. kinase (GAK), a cellular regulator of the clathrin-assocd. host adaptor proteins AP-1 and AP-2, regulates intracellular trafficking of multiple unrelated RNA viruses during early and late stages of the viral lifecycle. We also reported the discovery of potent, selective GAK inhibitors based on an isothiazolo[4,3-b]pyridine scaffold, albeit with moderate antiviral activity. Here, we describe our efforts leading to the discovery of novel isothiazolo[4,3-b]pyridines that maintain high GAK affinity and selectivity. These compds. demonstrate improved in vitro activity against dengue virus, including in human primary dendritic cells, and efficacy against the unrelated Ebola and chikungunya viruses. Moreover, inhibition of GAK activity was validated as an important mechanism of antiviral action of these compds. These findings demonstrate the potential utility of a GAK-targeted broad-spectrum approach for combating currently untreatable emerging viral infections.
- 298Glatthar, R.; Stojanovic, A.; Troxler, T.; Mattes, H.; Mobitz, H.; Beerli, R.; Blanz, J.; Gassmann, E.; Druckes, P.; Fendrich, G.; Gutmann, S.; Martiny-Baron, G.; Spence, F.; Hornfeld, J.; Peel, J. E.; Sparrer, H. Discovery of imidazoquinolines as a novel class of potent, selective, and in vivo efficacious cancer osaka thyroid (COT) kinase inhibitors. J. Med. Chem. 2016, 59, 7544– 7560, DOI: 10.1021/acs.jmedchem.6b00598[ACS Full Text], [CAS], Google Scholar298https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlSms7nN&md5=26f882f203e21bf78d9c9e5090f8fc5bDiscovery of Imidazoquinolines as a Novel Class of Potent, Selective, and in Vivo Efficacious Cancer Osaka Thyroid (COT) Kinase InhibitorsGlatthar, Ralf; Stojanovic, Aleksandar; Troxler, Thomas; Mattes, Henri; Mobitz, Henrik; Beerli, Rene; Blanz, Joachim; Gassmann, Ernst; Druckes, Peter; Fendrich, Gabriele; Gutmann, Sascha; Martiny-Baron, Georg; Spence, Fiona; Hornfeld, Jeff; Peel, John Edmonson; Sparrer, HelmutJournal of Medicinal Chemistry (2016), 59 (16), 7544-7560CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Cancer Osaka thyroid (COT) kinase is an important regulator of pro-inflammatory cytokines in macrophages. Thus, pharmacol. inhibition of COT should be a valid approach to therapeutically intervene in the pathogenesis of macrophage-driven inflammatory diseases such as rheumatoid arthritis. We report the discovery and chem. optimization of a novel series of COT kinase inhibitors, with unprecedented nanomolar potency for the inhibition of TNFα. Pharmacol. profiling in vivo revealed a high metab. of these compds. in rats which was demonstrated to be predominantly attributed to aldehyde oxidase. Due to the very low activity of hepatic AO in the dog, the selected candidate 32 displayed significant blood exposure in dogs which resulted in a clear prevention of inflammation-driven lameness. Taken together, the described compds. both potently and selectively inhibit COT kinase in primary human cells and ameliorate inflammatory pathologies in vivo, supporting the notion that COT is an appropriate therapeutic target for inflammatory diseases.
- 299Sun, Q. Z.; Lin, G. F.; Li, L. L.; Jin, X. T.; Huang, L. Y.; Zhang, G.; Yang, W.; Chen, K.; Xiang, R.; Chen, C.; Wei, Y. Q.; Lu, G. W.; Yang, S. Y. Discovery of potent and selective inhibitors of cdc2-like kinase 1 (CLK1) as a new class of autophagy inducers. J. Med. Chem. 2017, 60, 6337– 6352, DOI: 10.1021/acs.jmedchem.7b00665[ACS Full Text], [CAS], Google Scholar299https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFCmtLnE&md5=61f94754810e761bfbc2bd1fe19a1123Discovery of Potent and Selective Inhibitors of Cdc2-Like Kinase 1 (CLK1) as a New Class of Autophagy InducersSun, Qi-Zheng; Lin, Gui-Feng; Li, Lin-Li; Jin, Xi-Ting; Huang, Lu-Yi; Zhang, Guo; Yang, Wei; Chen, Kai; Xiang, Rong; Chen, Chong; Wei, Yu-Quan; Lu, Guang-Wen; Yang, Sheng-YongJournal of Medicinal Chemistry (2017), 60 (14), 6337-6352CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Autophagy inducers represent new promising agents for the treatment of a wide range of medical illnesses. However, safe autophagy inducers for clin. applications are lacking. Inhibition of cdc2-like kinase 1 (CLK1) was recently found to efficiently induce autophagy. Unfortunately, most of the known CLK1 inhibitors have unsatisfactory selectivity. Herein, we report the discovery of a series of new CLK1 inhibitors contg. the 1H-[1,2,3]triazolo[4,5-c]quinoline scaffold. Among them, compd. 25 was the most potent and selective, with an IC50 value of 2 nM against CLK1. The crystal structure of CLK1 complexed with compd. 25 was solved, and the potency and kinase selectivity of compd. 25 were interpreted. Compd. 25 was able to induce autophagy in in vitro assays and displayed significant hepatoprotective effects in the acetaminophen (APAP)-induced liver injury mouse model. Collectively, due to its potency and selectivity, compd. 25 could be used as a chem. probe or agent in future mechanism-of-action or autophagy-related disease therapy studies.
- 300Liachko, N. F.; McMillan, P. J.; Guthrie, C. R.; Bird, T. D.; Leverenz, J. B.; Kraemer, B. C. CDC7 inhibition blocks pathological TDP-43 phosphorylation and neurodegeneration. Ann. Neurol. 2013, 74, 39– 52, DOI: 10.1002/ana.23870[Crossref], [PubMed], [CAS], Google Scholar300https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtlKku7jF&md5=ef5b9758b78283441f7a7de22c8959b0CDC7 inhibition blocks pathological TDP-43 phosphorylation and neurodegenerationLiachko, Nicole F.; McMillan, Pamela J.; Guthrie, Chris R.; Bird, Thomas D.; Leverenz, James B.; Kraemer, Brian C.Annals of Neurology (2013), 74 (1), 39-52CODEN: ANNED3; ISSN:0364-5134. (Wiley-Liss, Inc.)Objective : Kinase hyperactivity occurs in both neurodegenerative disease and cancer. Lesions contg. hyperphosphorylated aggregated TDP-43 characterize amyotrophic lateral sclerosis and frontotemporal lobar degeneration with TDP-43 inclusions. Dual phosphorylation of TDP-43 at serines 409/410 (S409/410) drives neurotoxicity in disease models; therefore, TDP-43-specific kinases are candidate targets for intervention. Methods : To find therapeutic targets for the prevention of TDP-43 phosphorylation, we assembled and screened a comprehensive RNA interference library targeting kinases in TDP-43 transgenic Caenorhabditis elegans. Results : We show CDC7 robustly phosphorylates TDP-43 at pathol. residues S409/410 in C. elegans, in vitro, and in human cell culture. In frontotemporal lobar degeneration (FTLD)-TDP cases, CDC7 immunostaining overlaps with the phospho-TDP-43 pathol. found in frontal cortex. Furthermore, PHA767491, a small mol. inhibitor of CDC7, reduces TDP-43 phosphorylation and prevents TDP-43-dependent neurodegeneration in TDP-43-transgenic animals. Interpretation : Taken together, these data support CDC7 as a novel therapeutic target for TDP-43 proteinopathies, including FTLD-TDP and amyotrophic lateral sclerosis.
- 301Hazlitt, R. A.; Teitz, T.; Bonga, J. D.; Fang, J.; Diao, S.; Iconaru, L.; Yang, L.; Goktug, A. N.; Currier, D. G.; Chen, T.; Rankovic, Z.; Min, J.; Zuo, J. Development of second-generation CDK2 inhibitors for the prevention of cisplatin-induced hearing loss. J. Med. Chem. 2018, 61, 7700– 7709, DOI: 10.1021/acs.jmedchem.8b00669[ACS Full Text], [CAS], Google Scholar301https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsVOjsLvN&md5=ad407a81d1ee43b04f511f6fba8678d1Development of Second-Generation CDK2 Inhibitors for the Prevention of Cisplatin-Induced Hearing LossHazlitt, Robert A.; Teitz, Tal; Bonga, Justine D.; Fang, Jie; Diao, Shiyong; Iconaru, Luigi; Yang, Lei; Goktug, Asli N.; Currier, Duane G.; Chen, Taosheng; Rankovic, Zoran; Min, Jaeki; Zuo, JianJournal of Medicinal Chemistry (2018), 61 (17), 7700-7709CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)There are currently no FDA-approved therapies to prevent the hearing loss assocd. with the usage of cisplatin in chemotherapeutic regimens. We recently demonstrated that the pharmacol. inhibition with kenpaullone or genetic deletion of CDK2 preserved hearing function in animal models treated with cisplatin, which suggests that CDK2 is a promising therapeutic target to prevent cisplatin-induced ototoxicity. In this study, we identified two lead compds., AT7519 and AZD5438, from a focused library screen of 187 CDK2 inhibitors, performed in an immortalized cell line derived from neonatal mouse cochleae treated with cisplatin. Moreover, we screened 36 analogs of AT7519 and identified analog I, which exhibited an improved therapeutic index. When delivered locally, analog I and AZD5438 both provided significant protection against cisplatin-induced ototoxicity in mice. Thus, we have identified two addnl. compds. that prevent cisplatin-induced ototoxicity in vivo and provided further evidence that CDK2 is a druggable target for treating cisplatin-induced ototoxicity.
- 302Yang, L.; Gu, X.; Zhang, W.; Zhang, J.; Ma, Z. Cdk5 inhibitor roscovitine alleviates neuropathic pain in the dorsal root ganglia by downregulating N-methyl-D-aspartate receptor subunit 2A. Neurol Sci. 2014, 35, 1365– 1371, DOI: 10.1007/s10072-014-1713-9[Crossref], [PubMed], [CAS], Google Scholar302https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2crmsVagsg%253D%253D&md5=79f8b63373b76a67b6ba9deb8188a90eCdk5 inhibitor roscovitine alleviates neuropathic pain in the dorsal root ganglia by downregulating N-methyl-D-aspartate receptor subunit 2AYang Lei; Gu Xiaoping; Zhang Wei; Zhang Juan; Ma ZhengliangNeurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology (2014), 35 (9), 1365-71 ISSN:.Cyclin-dependent kinase 5 (Cdk5) is a member of the small proline-directed serine/threonine kinase family. Cdk5 is not involved in cell cycle regulation, but is implicated in neurodegenerative disorders. However, the role of Cdk5 in neuropathic pain remains unclear. This study aimed to evaluate the possibility that Cdk5 is involved in neuropathic pain in the dorsal root ganglia (DRG). We injected intrathecally Cdk5 inhibitor roscovitine in rat model of chronic compression of dorsal root ganglion and examined pain behaviors and the expression of N-methyl-d-aspartate receptor subunit 2A (NR2A) but not NR2B or NR1 in DRG. We found that roscovitine alleviated neuropathic pain, causing decline in paw withdrawal mechanical threshold and paw withdrawal thermal latency. Furthermore, roscovitine inhibited NR2A expression in DRG. These data suggest that Cdk5-NR2A pathway regulates neuropathic pain in DRG, and intrathecal injection of roscovitine could alleviate neuropathic pain. Our findings provide new insight into the analgesic effects of Roscovitine and identify Cdk5-NR2A pathway as a potential target for effective treatment of neuropathic pain.
- 303Fromont, C.; Atzori, A.; Kaur, D.; Hashmi, L.; Greco, G.; Cabanillas, A.; Nguyen, H. V.; Jones, D. H.; Garzon, M.; Varela, A.; Stevenson, B.; Iacobini, G. P.; Lenoir, M.; Rajesh, S.; Box, C.; Kumar, J.; Grant, P.; Novitskaya, V.; Morgan, J.; Sorrell, F. J.; Redondo, C.; Kramer, A.; Harris, C. J.; Leighton, B.; Vickers, S. P.; Cheetham, S. C.; Kenyon, C.; Grabowska, A. M.; Overduin, M.; Berditchevski, F.; Weston, C. J.; Knapp, S.; Fischer, P. M.; Butterworth, S. Discovery of highly selective inhibitors of Calmodulin-dependent kinases that restore insulin sensitivity in the diet-induced obesity in vivo mouse model. J. Med. Chem. 2020, 63, 6784– 6801, DOI: 10.1021/acs.jmedchem.9b01803[ACS Full Text], [CAS], Google Scholar303https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXpvFWqsLk%253D&md5=8eb74ed13110e8e35c04b85d84fca35cDiscovery of Highly Selective Inhibitors of Calmodulin-Dependent Kinases That Restore Insulin Sensitivity in the Diet-Induced Obesity in Vivo Mouse ModelFromont, Christophe; Atzori, Alessio; Kaur, Divneet; Hashmi, Lubna; Greco, Graziella; Cabanillas, Alejandro; Nguyen, Huy Van; Jones, D. Heulyn; Garzon, Miguel; Varela, Ana; Stevenson, Brett; Iacobini, Greg P.; Lenoir, Marc; Rajesh, Sundaresan; Box, Clare; Kumar, Jitendra; Grant, Paige; Novitskaya, Vera; Morgan, Juliet; Sorrell, Fiona J.; Redondo, Clara; Kramer, Andreas; Harris, C. John; Leighton, Brendan; Vickers, Steven P.; Cheetham, Sharon C.; Kenyon, Colin; Grabowska, Anna M.; Overduin, Michael; Berditchevski, Fedor; Weston, Chris J.; Knapp, Stefan; Fischer, Peter M.; Butterworth, SamJournal of Medicinal Chemistry (2020), 63 (13), 6784-6801CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Polymorphisms in the region of the calmodulin-dependent kinase isoform D (CaMK1D) gene are assocd. with increased incidence of diabetes, with the most common polymorphism resulting in increased recognition by transcription factors and increased protein expression. While reducing CaMK1D expression has a potentially beneficial effect on glucose processing in human hepatocytes, there are no known selective inhibitors of CaMK1 kinases that can be used to validate or translate these findings. Here we describe the development of a series of potent, selective, and drug-like CaMK1 inhibitors that are able to provide significant free target cover in mouse models and are therefore useful as in vivo tool compds. Our results show that a lead compd. from this series improves insulin sensitivity and glucose control in the diet-induced obesity mouse model after both acute and chronic administration, providing the first in vivo validation of CaMK1D as a target for diabetes therapeutics.
- 304Xie, Z.; Wu, B.; Liu, Y.; Ren, W.; Tong, L.; Xiang, C.; Wei, A.; Gao, Y.; Zeng, L.; Xie, H.; Tang, W.; Hu, Y. Novel class of Colony-stimulating factor 1 receptor kinase inhibitors based on an o-aminopyridyl alkynyl scaffold as potential treatment for inflammatory disorders. J. Med. Chem. 2020, 63, 1397– 1414, DOI: 10.1021/acs.jmedchem.9b01912[ACS Full Text], [CAS], Google Scholar304https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXnsl2guw%253D%253D&md5=8e35b5e75e5a657d6714156a708806a2Novel Class of Colony-Stimulating Factor 1 Receptor Kinase Inhibitors Based on an o-Aminopyridyl Alkynyl Scaffold as Potential Treatment for Inflammatory DisordersXie, Zhicheng; Wu, Bing; Liu, Yingqiang; Ren, Wenming; Tong, Linjiang; Xiang, Caigui; Wei, Aihuan; Gao, Yuanzhuo; Zeng, Limin; Xie, Hua; Tang, Wei; Hu, YouhongJournal of Medicinal Chemistry (2020), 63 (3), 1397-1414CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Colony-stimulating factor 1 receptor (CSF-1R) is involved in inflammatory disorders as well as in many types of cancer. Based on high-throughput screening and docking results, we performed a detailed structure-activity-relationship study, leading to the discovery of a new series of compds. with nanomolar IC50 values against CSF-1R without the inhibition of fibroblast growth factor receptors. One of the most promising hits, compd. 29, potently inhibited CSF-1R kinase with an IC50 value of 0.7 nM, while it showed no inhibition to the same family member FMS-like tyrosine kinase 3. Compd. 29 displayed excellent anti-inflammatory effects against RAW264.7 macrophages indicated by significant inhibition against the activation of the CSF-1R pathway with low cytotoxicity. In addn., compd. 29 exhibited strong in vivo anti-inflammatory efficacy alongside favorable drug characteristics. This novel compd. 29 may serve as a new drug candidate with promising applications in inflammatory disorders.
- 305El-Gamal, M. I.; Al-Ameen, S. K.; Al-Koumi, D. M.; Hamad, M. G.; Jalal, N. A.; Oh, C. H. Recent advances of colony-stimulating factor-1 receptor (CSF-1R) kinase and its inhibitors. J. Med. Chem. 2018, 61, 5450– 5466, DOI: 10.1021/acs.jmedchem.7b00873[ACS Full Text], [CAS], Google Scholar305https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvVWgtg%253D%253D&md5=9fa615ecf2f532f1a2f1bac1e4c48932Recent Advances of Colony-Stimulating Factor-1 Receptor (CSF-1R) Kinase and Its InhibitorsEl-Gamal, Mohammed I.; Al-Ameen, Shahad K.; Al-Koumi, Dania M.; Hamad, Mawadda G.; Jalal, Nouran A.; Oh, Chang-HyunJournal of Medicinal Chemistry (2018), 61 (13), 5450-5466CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Colony stimulation factor-1 receptor (CSF-1R), which is also known as FMS kinase, plays an important role in initiating inflammatory, cancer, and bone disorders when it is over-stimulated by its ligand, CSF-1. Innate immunity, as well as macrophage differentiation and survival, are regulated by the stimulation of the CSF-1R. Another ligand, interleukin-34 (IL-34), was recently reported to activate the CSF-1R receptor in a different manner. The relationship between CSF-1R and microglia has been reviewed. Both CSF-1 antibodies and small mol. CSF-1R kinase inhibitors have now been tested in animal models and in humans. In this Perspective, the authors discuss the role of CSF-1 and IL-34 in producing cancer, bone disorders, and inflammation. The authors also review the newly discovered and improved small mol. kinase inhibitors and monoclonal antibodies that have shown potent activity toward CSF-1R, reported from 2012 until 2017.
- 306Czarna, A.; Wang, J.; Zelencova, D.; Liu, Y.; Deng, X.; Choi, H. G.; Zhang, T.; Zhou, W.; Chang, J. W.; Kildalsen, H.; Seternes, O. M.; Gray, N. S.; Engh, R. A.; Rothweiler, U. Novel scaffolds for dual specificity tyrosine-phosphorylation-regulated kinase (DYRK1A) inhibitors. J. Med. Chem. 2018, 61, 7560– 7572, DOI: 10.1021/acs.jmedchem.7b01847[ACS Full Text], [CAS], Google Scholar306https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsVygtrjF&md5=c4b55fc7510b9f9d80726933b32be508Novel Scaffolds for Dual Specificity Tyrosine-Phosphorylation-Regulated Kinase (DYRK1A) InhibitorsCzarna, Anna; Wang, Jinhua; Zelencova, Diana; Liu, Yao; Deng, Xianming; Choi, Hwan Geun; Zhang, Tinghu; Zhou, Wenjun; Chang, Jae Won; Kildalsen, Hanne; Seternes, Ole Morten; Gray, Nathanael S.; Engh, Richard A.; Rothweiler, UlliJournal of Medicinal Chemistry (2018), 61 (17), 7560-7572CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)DYRK1A is one of five members of the dual-specificity tyrosine (Y) phosphorylation-regulated kinase (DYRK) family. The DYRK1A gene is located in the Down syndrome crit. region and regulates cellular processes related to proliferation and differentiation of neuronal progenitor cells during early development. This has focused research on its role in neuronal degenerative diseases, including Alzheimer's and Down syndrome. Recent studies have also shown a possible role of DYRK1A in diabetes. Here we report a variety of scaffolds not generally known for DYRK1A inhibition, demonstrating their effects in in vitro assays and also in cell cultures. These inhibitors effectively block the tau phosphorylation that is a hallmark of Alzheimer's disease. The crystal structures of these inhibitors support the design of optimized and novel therapeutics.
- 307Kumar, K.; Wang, P.; Wilson, J.; Zlatanic, V.; Berrouet, C.; Khamrui, S.; Secor, C.; Swartz, E. A.; Lazarus, M.; Sanchez, R.; Stewart, A. F.; Garcia-Ocana, A.; DeVita, R. J. Synthesis and biological validation of a harmine-based, central nervous system (CNS)-avoidant, selective, human β-cell regenerative Dual-specificity tyrosine phosphorylation-regulated kinase A (DYRK1A) inhibitor. J. Med. Chem. 2020, 63, 2986– 3003, DOI: 10.1021/acs.jmedchem.9b01379[ACS Full Text], [CAS], Google Scholar307https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitVOgsr8%253D&md5=c739edc1358acafc412a122c272edcebSynthesis and Biological Validation of a Harmine-Based, Central Nervous System (CNS)-Avoidant, Selective, Human β-Cell Regenerative Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase A (DYRK1A) InhibitorKumar, Kunal; Wang, Peng; Wilson, Jessica; Zlatanic, Viktor; Berrouet, Cecilia; Khamrui, Susmita; Secor, Cody; Swartz, Ethan A.; Lazarus, Michael; Sanchez, Roberto; Stewart, Andrew F.; Garcia-Ocana, Adolfo; DeVita, Robert J.Journal of Medicinal Chemistry (2020), 63 (6), 2986-3003CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Recently, our group identified that harmine is able to induce β-cell proliferation both in vitro and in vivo, mediated via the DYRK1A-NFAT pathway. Since, harmine suffers from a lack of selectivity, both against other kinases and CNS off-targets, we therefore sought to expand structure-activity relationships for harmine's DYRK1A activity, to enhance selectivity for off-targets while retaining human β-cell proliferation activity. We carried out optimization of the 9-N-position of harmine to synthesize 29 harmine-based analogs. Several novel inhibitors showed excellent DYRK1A inhibition and human β-cell proliferation capability. An optimized DYRK1A inhibitor, compd. I, was identified as a novel, efficacious in vivo lead candidate. Compd. I also demonstrates improved selectivity for kinases and CNS off-targets, as well as in vivo efficacy for β-cell proliferation and regeneration at lower doses than harmine. Collectively, these findings demonstrate that compd. I is a much improved in vivo lead candidate as compared to harmine for the treatment of diabetes.
- 308Liu, Y. A.; Jin, Q.; Zou, Y.; Ding, Q.; Yan, S.; Wang, Z.; Hao, X.; Nguyen, B.; Zhang, X.; Pan, J.; Mo, T.; Jacobsen, K.; Lam, T.; Wu, T. Y.; Petrassi, H. M.; Bursulaya, B.; DiDonato, M.; Gordon, W. P.; Liu, B.; Baaten, J.; Hill, R.; Nguyen-Tran, V.; Qiu, M.; Zhang, Y. Q.; Kamireddy, A.; Espinola, S.; Deaton, L.; Ha, S.; Harb, G.; Jia, Y.; Li, J.; Shen, W.; Schumacher, A. M.; Colman, K.; Glynne, R.; Pan, S.; McNamara, P.; Laffitte, B.; Meeusen, S.; Molteni, V.; Loren, J. Selective DYRK1A inhibitor for the treatment of type 1 diabetes: discovery of 6-azaindole derivative GNF2133. J. Med. Chem. 2020, 63, 2958– 2973, DOI: 10.1021/acs.jmedchem.9b01624[ACS Full Text], [CAS], Google Scholar308https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXjtlSqs7g%253D&md5=0ec2402f79b1b3fa338aab9672b8b669Selective DYRK1A Inhibitor for the Treatment of Type 1 Diabetes: Discovery of 6-Azaindole Derivative GNF2133Liu, Yahu A.; Jin, Qihui; Zou, Yefen; Ding, Qiang; Yan, Shanshan; Wang, Zhicheng; Hao, Xueshi; Nguyen, Bao; Zhang, Xiaoyue; Pan, Jianfeng; Mo, Tingting; Jacobsen, Kate; Lam, Thanh; Wu, Tom Y.-H.; Petrassi, H. Michael; Bursulaya, Badry; Di Donato, Michael; Gordon, W. Perry; Liu, Bo; Baaten, Janine; Hill, Robert; Nguyen-Tran, Van; Qiu, Minhua; Zhang, You-Qing; Kamireddy, Anwesh; Espinola, Sheryll; Deaton, Lisa; Ha, Sukwon; Harb, George; Jia, Yong; Li, Jing; Shen, Weijun; Schumacher, Andrew M.; Colman, Karyn; Glynne, Richard; Pan, Shifeng; McNamara, Peter; Laffitte, Bryan; Meeusen, Shelly; Molteni, Valentina; Loren, JonJournal of Medicinal Chemistry (2020), 63 (6), 2958-2973CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Autoimmune deficiency and destruction in either β-cell mass or function can cause insufficient insulin levels and, as a result, hyperglycemia and diabetes. Thus, promoting β-cell proliferation could be one approach toward diabetes intervention. In this report we describe the discovery of a potent and selective DYRK1A inhibitor GNF2133, which was identified through optimization of a 6-azaindole screening hit. In vitro, GNF2133 is able to proliferate both rodent and human β-cells. In vivo, GNF2133 demonstrated significant dose-dependent glucose disposal capacity and insulin secretion in response to glucose-potentiated arginine-induced insulin secretion (GPAIS) challenge in rat insulin promoter and diphtheria toxin A (RIP-DTA) mice. The work described here provides new avenues to disease altering therapeutic interventions in the treatment of type 1 diabetes (T1D).
- 309Siu, M.; Sengupta Ghosh, A.; Lewcock, J. W. Dual leucine zipper kinase inhibitors for the treatment of neurodegeneration. J. Med. Chem. 2018, 61, 8078– 8087, DOI: 10.1021/acs.jmedchem.8b00370[ACS Full Text], [CAS], Google Scholar309https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVGiu7bN&md5=a13dd92c10d63a0a37bc011efb27f67cDual Leucine Zipper Kinase Inhibitors for the Treatment of NeurodegenerationSiu, Michael; Sengupta Ghosh, Arundhati; Lewcock, Joseph W.Journal of Medicinal Chemistry (2018), 61 (18), 8078-8087CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Dual leucine zipper kinase (DLK, MAP3K12) is an essential driver of the neuronal stress response that regulates neurodegeneration in models of acute neuronal injury and chronic neurodegenerative diseases such as Alzheimer's, Parkinson's, and ALS. In this review, we provide an overview of DLK signaling mechanisms and describe selected small mols. that have been utilized to inhibit DLK kinase activity in vivo. These compds. represent valuable tools for understanding the role of DLK signaling and evaluating the potential for DLK inhibition as a therapeutic strategy to prevent neuronal degeneration.
- 310Patel, S.; Cohen, F.; Dean, B. J.; De La Torre, K.; Deshmukh, G.; Estrada, A. A.; Ghosh, A. S.; Gibbons, P.; Gustafson, A.; Huestis, M. P.; Le Pichon, C. E.; Lin, H.; Liu, W.; Liu, X.; Liu, Y.; Ly, C. Q.; Lyssikatos, J. P.; Ma, C.; Scearce-Levie, K.; Shin, Y. G.; Solanoy, H.; Stark, K. L.; Wang, J.; Wang, B.; Zhao, X.; Lewcock, J. W.; Siu, M. Discovery of dual leucine zipper kinase (DLK, MAP3K12) inhibitors with activity in neurodegeneration models. J. Med. Chem. 2015, 58, 401– 418, DOI: 10.1021/jm5013984[ACS Full Text], [CAS], Google Scholar310https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVSjsr3P&md5=8f4ebdbfb0d324a4253bcd832e690a18Discovery of Dual Leucine Zipper Kinase (DLK, MAP3K12) Inhibitors with Activity in Neurodegeneration ModelsPatel, Snahel; Cohen, Frederick; Dean, Brian J.; De La Torre, Kelly; Deshmukh, Gauri; Estrada, Anthony A.; Ghosh, Arundhati Sengupta; Gibbons, Paul; Gustafson, Amy; Huestis, Malcolm P.; Le Pichon, Claire E.; Lin, Han; Liu, Wendy; Liu, Xingrong; Liu, Yichin; Ly, Cuong Q.; Lyssikatos, Joseph P.; Ma, Changyou; Scearce-Levie, Kimberly; Shin, Young G.; Solanoy, Hilda; Stark, Kimberly L.; Wang, Jian; Wang, Bei; Zhao, Xianrui; Lewcock, Joseph W.; Siu, MichaelJournal of Medicinal Chemistry (2015), 58 (1), 401-418CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Dual leucine zipper kinase (DLK, MAP3K12) was recently identified as an essential regulator of neuronal degeneration in multiple contexts. Here the authors describe the generation of potent and selective DLK inhibitors starting from a high-throughput screening hit. Using proposed hinge-binding interactions to infer a binding mode and specific design parameters to optimize for CNS druglike mols., the authors came to focus on the di(pyridin-2-yl)amines because of their combination of desirable potency and good brain penetration following oral dosing. The lead inhibitor GNE-3511 I displayed concn.-dependent protection of neurons from degeneration in vitro and demonstrated dose-dependent activity in two different animal models of disease. These results suggest that specific pharmacol. inhibition of DLK may have therapeutic potential in multiple indications.
- 311Patel, S.; Harris, S. F.; Gibbons, P.; Deshmukh, G.; Gustafson, A.; Kellar, T.; Lin, H.; Liu, X.; Liu, Y.; Liu, Y.; Ma, C.; Scearce-Levie, K.; Ghosh, A. S.; Shin, Y. G.; Solanoy, H.; Wang, J.; Wang, B.; Yin, J.; Siu, M.; Lewcock, J. W. Scaffold-hopping and structure-based discovery of potent, selective, and brain penetrant N-(1H-pyrazol-3-yl)pyridin-2-amine inhibitors of dual Leucine zipper kinase (DLK, MAP3K12). J. Med. Chem. 2015, 58, 8182– 8199, DOI: 10.1021/acs.jmedchem.5b01072[ACS Full Text], [CAS], Google Scholar311https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1Kit7fN&md5=e7b850d7c7d2eac3317b573ace2c6fabScaffold-Hopping and Structure-Based Discovery of Potent, Selective, And Brain Penetrant N-(1H-Pyrazol-3-yl)pyridin-2-amine Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12)Patel, Snahel; Harris, Seth F.; Gibbons, Paul; Deshmukh, Gauri; Gustafson, Amy; Kellar, Terry; Lin, Han; Liu, Xingrong; Liu, Yanzhou; Liu, Yichin; Ma, Changyou; Scearce-Levie, Kimberly; Ghosh, Arundhati Sengupta; Shin, Young G.; Solanoy, Hilda; Wang, Jian; Wang, Bei; Yin, Jianping; Siu, Michael; Lewcock, Joseph W.Journal of Medicinal Chemistry (2015), 58 (20), 8182-8199CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Recent data suggest that inhibition of dual leucine zipper kinase (DLK, MAP3K12) has therapeutic potential for treatment of a no. of indications ranging from acute neuronal injury to chronic neurodegenerative disease. Thus, high demand exists for selective small mol. DLK inhibitors with favorable drug-like properties and good CNS penetration. Herein the authors describe a shape-based scaffold hopping approach to convert pyrimidine 1 to a pyrazole core with improved physicochem. properties. The authors also present the first crystal structures of DLK. By utilizing a combination of property and structure-based design, the authors identified inhibitor I, a potent, selective, and brain-penetrant inhibitor of DLK with activity in an in vivo nerve injury model.
- 312Patel, S.; Meilandt, W. J.; Erickson, R. I.; Chen, J.; Deshmukh, G.; Estrada, A. A.; Fuji, R. N.; Gibbons, P.; Gustafson, A.; Harris, S. F.; Imperio, J.; Liu, W.; Liu, X.; Liu, Y.; Lyssikatos, J. P.; Ma, C.; Yin, J.; Lewcock, J. W.; Siu, M. Selective inhibitors of dual Leucine zipper kinase (DLK, MAP3K12) with activity in a model of Alzheimer’s disease. J. Med. Chem. 2017, 60, 8083– 8102, DOI: 10.1021/acs.jmedchem.7b00843[ACS Full Text], [CAS], Google Scholar312https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFWhsL%252FF&md5=bda6dd84d0c56e3a9c9849c9de69233eSelective Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12) with Activity in a Model of Alzheimer's DiseasePatel, Snahel; Meilandt, William J.; Erickson, Rebecca I.; Chen, Jinhua; Deshmukh, Gauri; Estrada, Anthony A.; Fuji, Reina N.; Gibbons, Paul; Gustafson, Amy; Harris, Seth F.; Imperio, Jose; Liu, Wendy; Liu, Xingrong; Liu, Yichin; Lyssikatos, Joseph P.; Ma, Changyou; Yin, Jianping; Lewcock, Joseph W.; Siu, MichaelJournal of Medicinal Chemistry (2017), 60 (19), 8083-8102CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Significant data exists to suggest that dual leucine zipper kinase (DLK, MAP3K12) is a conserved regulator of neuronal degeneration following neuronal injury and in chronic neurodegenerative disease. Consequently, there is considerable interest in the identification of DLK inhibitors with a profile compatible with development for these indications. Herein, we use structure-based drug design combined with a focus on CNS drug-like properties to generate compds. with superior kinase selectivity and metabolic stability as compared to previously disclosed DLK inhibitors. These compds., exemplified by inhibitor 14, retain excellent CNS penetration and are well tolerated following multiple days of dosing at concns. that exceed those required for DLK inhibition in the brain.
- 313Wu, B.; De, S. K.; Kulinich, A.; Salem, A. F.; Koeppen, J.; Wang, R.; Barile, E.; Wang, S.; Zhang, D.; Ethell, I.; Pellecchia, M. Potent and selective EphA4 agonists for the treatment of ALS. Cell Chem. Biol. 2017, 24, 293– 305, DOI: 10.1016/j.chembiol.2017.01.006[Crossref], [PubMed], [CAS], Google Scholar313https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXisF2isLw%253D&md5=4701fc563841cf233e9e8c8ac7c256f7Potent and Selective EphA4 Agonists for the Treatment of ALSWu, Bainan; De, Surya K.; Kulinich, Anna; Salem, Ahmed F.; Koeppen, Jordan; Wang, Rengang; Barile, Elisa; Wang, Si; Zhang, Dongxiang; Ethell, Iryna; Pellecchia, MaurizioCell Chemical Biology (2017), 24 (3), 293-305CODEN: CCBEBM; ISSN:2451-9448. (Cell Press)Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease that affects motor neurons. Recent studies identified the receptor tyrosine kinase EphA4 as a disease-modifying gene that is crit. for the progression of motor neuron degeneration. We report on the design and characterization of a family of EphA4 targeting agents that bind to its ligand binding domain with nanomolar affinity. The mols. exhibit excellent selectivity and display efficacy in a SOD1 mutant mouse model of ALS. Interestingly, the mols. appear to act as agonists for the receptor in certain surrogate cellular assays. While the exact mechanisms responsible for the therapeutic effect of the new agonists remain to be elucidated, we believe that the described agent represents both an invaluable pharmacol. tool to further decipher the role of the EphA4 in ALS and potentially other human diseases, and a significant stepping stone for the development of novel treatments.
- 314Ziegelbauer, K.; Gantner, F.; Lukacs, N. W.; Berlin, A.; Fuchikami, K.; Niki, T.; Sakai, K.; Inbe, H.; Takeshita, K.; Ishimori, M.; Komura, H.; Murata, T.; Lowinger, T.; Bacon, K. B. A selective novel low-molecular-weight inhibitor of IκB kinase-β (IKK-β) prevents pulmonary inflammation and shows broad anti-inflammatory activity. Br. J. Pharmacol. 2005, 145, 178– 192, DOI: 10.1038/sj.bjp.0706176[Crossref], [PubMed], [CAS], Google Scholar314https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXkt1Shtbc%253D&md5=1cc77dccfe9f693ae5badda3565c634eA selective novel low-molecular-weight inhibitor of IκB kinase-β (IKK-β) prevents pulmonary inflammation and shows broad anti-inflammatory activityZiegelbauer, Karl; Gantner, Florian; Lukacs, Nicholas W.; Berlin, Aaron; Fuchikami, Kinji; Niki, Toshiro; Sakai, Katsuya; Inbe, Hisayo; Takeshita, Keisuke; Ishimori, Mina; Komura, Hiroshi; Murata, Toshiki; Lowinger, Timothy; Bacon, Kevin B.British Journal of Pharmacology (2005), 145 (2), 178-192CODEN: BJPCBM; ISSN:0007-1188. (Nature Publishing Group)Pulmonary inflammatory diseases such as asthma are characterized by chronic, cell-mediated inflammation of the bronchial mucosa. Recruitment and activation of inflammatory cells is orchestrated by a variety of mediators such as cytokines, chemokines, or adhesion mols., the expression of which is regulated via the transcription factor nuclear factor kappa B (NF-κB). NF-κB signaling is controlled by the inhibitor of kappa B kinase complex (IKK), a crit. catalytic subunit of which is IKK-β. We identified Compd. A (7-[2-(cyclopropylmethoxy)6-hydroxyphenyl]-5-[(3S)-3-piperidinyl]-1,4-dihydro-2H-pyrido[2,3,-d][1,3]oxazin-2-one hydrochloride) as a small-mol., ATP-competitive inhibitor selectively targeting IKK-β kinase activity with a Ki value of 2 nM. Compd. A inhibited stress-induced NF-κB transactivation, chemokine-, cytokine-, and adhesion mol. expression, and T- and B-cell proliferation. Compd. A is orally bioavailable and inhibited the release of LPS-induced TNF-α in rodents. In mice Compd. A inhibited cockroach allergen-induced airway inflammation and hyperreactivity and efficiently abrogated leukocyte trafficking induced by carrageenan in mice or by ovalbumin in a rat model of airway inflammation. Compd. A was well tolerated by rodents over 3 wk without affecting wt. gain. Furthermore, in mice Compd. A suppressed edema formation in response to arachidonic acid, phorbol ester, or edema induced by delayed-type hypersensitivity. These data suggest that IKK-β inhibitors offer an effective therapeutic approach for inhibiting chronic pulmonary inflammation.
- 315Li, J.; Dong, R.; Yu, J.; Yi, S.; Da, J.; Yu, F.; Zha, Y. Inhibitor of IGF1 receptor alleviates the inflammation process in the diabetic kidney mouse model without activating SOCS2. Drug Des., Dev. Ther. 2018, 12, 2887– 2896, DOI: 10.2147/DDDT.S171638[Crossref], [PubMed], [CAS], Google Scholar315https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhslGru7%252FO&md5=739939a620fedf78ec8e09e1349fa43aInhibitor of IG F1 receptor alleviates the inflammation process in the diabetic kidney mouse model without activating SOCS2Li, Jiayu; Dong, Rong; Yu, Jiali; Yi, Sun; Da, Jingjing; Yu, Fuxun; Zha, YanDrug Design, Development and Therapy (2018), 12 (), 2887-2896CODEN: DDDTAQ; ISSN:1177-8881. (Dove Medical Press Ltd.)Objective: To explore the anti-inflammatory mechanism of IGF1R inhibitor in diabetic nephropathy. Methods: C57/BL6 mice were reared with high-fat diet for 8 wk, then were injected 30 mg/kg streptozotocin i.p. to induce type 2 diabetes. After 8 wk, the type 2 diabetes nephropathy model was successfully set up the different drugs were administrated to mice with diabetes (insulin 1-2 U/day, benazepril 10 mg/kg per day intragastrically, IGF-1R inhibitor 30 mg/kg per day intragastrically). After 8 wk drugs administration, all mice were collected the kidney tissue, measured levels of inflammatory factor (F4/80, TLR4and CD68) and fibrosis markers(αSMA, E-cadherin and SR) using immunohistochem. and in situ hybridization. Results: The type 2 diabetes nephropathy model was built successfully, which along with increased urinary protein excretion rate and increased inflammatory infiltration, and the correlation was characterized by increased CD68+, F4/80+ cells and increased TLR4, αSMA, SR expression. IGF-1R inhibitors reversed this changes, but benazepril and insulin were without significant changes. The insulin decreased the expression level of IGF-1, and increased the levels of suppressor of cytokine signaling 2 (SOCS2). Benazepril and IGF-1R inhibitor were no significant changes like insulin. Conclusion: Inhibition of IGF1R was a more effective choice for inflammation treatment than Ben or Ins in diabetic kidney disease (DKD). The IGF1R inhibitor blocked pathol. changes induced by the over-expression of IGF1 in DKD without up-regulating SOCS2 protein levels.
- 316Zapf, C. W.; Gerstenberger, B. S.; Xing, L.; Limburg, D. C.; Anderson, D. R.; Caspers, N.; Han, S.; Aulabaugh, A.; Kurumbail, R.; Shakya, S.; Li, X.; Spaulding, V.; Czerwinski, R. M.; Seth, N.; Medley, Q. G. Covalent inhibitors of interleukin-2 inducible T cell kinase (itk) with nanomolar potency in a whole-blood assay. J. Med. Chem. 2012, 55, 10047– 10063, DOI: 10.1021/jm301190s[ACS Full Text], [CAS], Google Scholar316https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFOlsbnP&md5=7e39a17151dc9493d13439bc48fa83a3Covalent Inhibitors of Interleukin-2 Inducible T Cell Kinase (Itk) with Nanomolar Potency in a Whole-Blood AssayZapf, Christoph W.; Gerstenberger, Brian S.; Xing, Li; Limburg, David C.; Anderson, David R.; Caspers, Nicole; Han, Seungil; Aulabaugh, Ann; Kurumbail, Ravi; Shakya, Subarna; Li, Xin; Spaulding, Vikki; Czerwinski, Robert M.; Seth, Nilufer; Medley, Quintus G.Journal of Medicinal Chemistry (2012), 55 (22), 10047-10063CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)We wish to report a strategy that targets interleukin-2 inducible T cell kinase (Itk) with covalent inhibitors. Thus far, covalent inhibition of Itk has not been disclosed in the literature. Structure-based drug design was utilized to achieve low nanomolar potency of the disclosed series even at high ATP concns. Kinetic measurements confirmed an irreversible binding mode with off-rate half-lives exceeding 24 h and moderate on-rates. The analogs are highly potent in a cellular IP1 assay as well as in a human whole-blood (hWB) assay. Despite a half-life of approx. 2 h in resting primary T cells, the covalent inhibition of Itk resulted in functional silencing of the TCR pathway for more than 24 h. This prolonged effect indicates that covalent inhibition is a viable strategy to target the inactivation of Itk.
- 317Burch, J. D.; Lau, K.; Barker, J. J.; Brookfield, F.; Chen, Y.; Chen, Y.; Eigenbrot, C.; Ellebrandt, C.; Ismaili, M. H. A.; Johnson, A.; Kordt, D.; MacKinnon, C. H.; McEwan, P. A.; Ortwine, D. F.; Stein, D. B.; Wang, X.; Winkler, D.; Yuen, P.-W.; Zhang, Y.; Zarrin, A. A.; Pei, Z. Property- and structure-guided discovery of a tetrahydroindazole series of interleukin-2 inducible T-cell kinase inhibitors. J. Med. Chem. 2014, 57, 5714– 5727, DOI: 10.1021/jm500550e[ACS Full Text], [CAS], Google Scholar317https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXps1Srtrs%253D&md5=636420d73f6ad55bf5391b6c6aeb3dbdProperty- and Structure-Guided Discovery of a Tetrahydroindazole Series of Interleukin-2 Inducible T-Cell Kinase InhibitorsBurch, Jason D.; Lau, Kevin; Barker, John J.; Brookfield, Fred; Chen, Yong; Chen, Yuan; Eigenbrot, Charles; Ellebrandt, Claire; Ismaili, M. Hicham A.; Johnson, Adam; Kordt, Daniel; MacKinnon, Colin H.; McEwan, Paul A.; Ortwine, Daniel F.; Stein, Daniel B.; Wang, Xiaolu; Winkler, Dirk; Yuen, Po-Wai; Zhang, Yamin; Zarrin, Ali A.; Pei, ZhonghuaJournal of Medicinal Chemistry (2014), 57 (13), 5714-5727CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Interleukin-2 inducible T-cell kinase (ITK), a member of the Tec family of tyrosine kinases, plays a major role in T-cell signaling downstream of the T-cell receptor (TCR), and considerable efforts have been directed toward discovery of ITK-selective inhibitors as potential treatments of inflammatory disorders such as asthma. Using a previously disclosed indazole series of inhibitors as a starting point, and using x-ray crystallog. and soly. forecast index (SFI) as guides, we evolved a series of tetrahydroindazole inhibitors with improved potency, selectivity, and pharmaceutical properties. Highlights include identification of a selectivity pocket above the ligand plane, and identification of appropriate lipophilic substituents to occupy this space. This effort culminated in identification of a potent and selective ITK inhibitor (GNE-9822) with good ADME properties in preclin. species.
- 318Burch, J. D.; Barrett, K.; Chen, Y.; DeVoss, J.; Eigenbrot, C.; Goldsmith, R.; Ismaili, M. H. A.; Lau, K.; Lin, Z.; Ortwine, D. F.; Zarrin, A. A.; McEwan, P. A.; Barker, J. J.; Ellebrandt, C.; Kordt, D.; Stein, D. B.; Wang, X.; Chen, Y.; Hu, B.; Xu, X.; Yuen, P.-W.; Zhang, Y.; Pei, Z. Tetrahydroindazoles as interleukin-2 inducible t-cell kinase inhibitors. Part II. Second-generation analogues with enhanced potency, selectivity, and pharmacodynamic modulation in vivo. J. Med. Chem. 2015, 58, 3806– 3816, DOI: 10.1021/jm501998m[ACS Full Text], [CAS], Google Scholar318https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXlvVaktbo%253D&md5=59a2cd1c2c9d368f9b49344af9b75545Tetrahydroindazoles as Interleukin-2 Inducible T-Cell Kinase Inhibitors. Part II. Second-Generation Analogues with Enhanced Potency, Selectivity, and Pharmacodynamic Modulation in VivoBurch, Jason D.; Barrett, Kathy; Chen, Yuan; DeVoss, Jason; Eigenbrot, Charles; Goldsmith, Richard; Ismaili, M. Hicham A.; Lau, Kevin; Lin, Zhonghua; Ortwine, Daniel F.; Zarrin, Ali A.; McEwan, Paul A.; Barker, John J.; Ellebrandt, Claire; Kordt, Daniel; Stein, Daniel B.; Wang, Xiaolu; Chen, Yong; Hu, Baihua; Xu, Xiaofeng; Yuen, Po-Wai; Zhang, Yamin; Pei, ZhonghuaJournal of Medicinal Chemistry (2015), 58 (9), 3806-3816CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The medicinal chem. community has directed considerable efforts toward the discovery of selective inhibitors of interleukin-2 inducible T-cell kinase (ITK), given its role in T-cell signaling downstream of the T-cell receptor (TCR) and the implications of this target for inflammatory disorders such as asthma. The authors have previously disclosed a structure- and property-guided lead optimization effort which resulted in the discovery of a new series of tetrahydroindazole-contg. selective ITK inhibitors. Herein the authors disclose further optimization of this series that resulted in further potency improvements, reduced off-target receptor binding liabilities, and reduced cytotoxicity. Specifically, the authors have identified a correlation between the basicity of solubilizing elements in the ITK inhibitors and off-target antiproliferative effects, which was exploited to reduce cytotoxicity while maintaining kinase selectivity. Optimized analogs, e.g. I, were shown to reduce IL-2 and IL-13 prodn. in vivo following oral or i.p. dosing in mice.
- 319Heifetz, A.; Trani, G.; Aldeghi, M.; MacKinnon, C. H.; McEwan, P. A.; Brookfield, F. A.; Chudyk, E. I.; Bodkin, M.; Pei, Z.; Burch, J. D.; Ortwine, D. F. Fragment molecular orbital method applied to lead optimization of novel interleukin-2 inducible T-cell kinase (ITK) inhibitors. J. Med. Chem. 2016, 59, 4352– 4363, DOI: 10.1021/acs.jmedchem.6b00045[ACS Full Text], [CAS], Google Scholar319https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xjs12jt70%253D&md5=b0958d9c29f7d61aadcc730ac00e8f90Fragment Molecular Orbital Method Applied to Lead Optimization of Novel Interleukin-2 Inducible T-Cell Kinase (ITK) InhibitorsHeifetz, Alexander; Trani, Giancarlo; Aldeghi, Matteo; MacKinnon, Colin H.; McEwan, Paul A.; Brookfield, Frederick A.; Chudyk, Ewa I.; Bodkin, Mike; Pei, Zhonghua; Burch, Jason D.; Ortwine, Daniel F.Journal of Medicinal Chemistry (2016), 59 (9), 4352-4363CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Inhibition of inducible T-cell kinase (ITK), a nonreceptor tyrosine kinase, may represent a novel treatment for allergic asthma. In our previous reports, we described the discovery of sulfonylpyridine (SAP), benzothiazole (BZT), indazole (IND), and tetrahydroindazole (THI) series as novel ITK inhibitors and how computational tools such as dihedral scans and docking were used to support this process. X-ray crystallog. and modeling were applied to provide essential insight into ITK-ligand interactions. However, "visual inspection" traditionally used for the rationalization of protein-ligand affinity cannot always explain the full complexity of the mol. interactions. The fragment MO (FMO) quantum-mech. (QM) method provides a complete list of the interactions formed between the ligand and protein that are often omitted from traditional structure-based descriptions. FMO methodol. was successfully used as part of a rational structure-based drug design effort to improve the ITK potency of high-throughput screening hits, ultimately delivering ligands with potency in the subnanomolar range.
- 320Yin, Y.; Zheng, K.; Eid, N.; Howard, S.; Jeong, J. H.; Yi, F.; Guo, J.; Park, C. M.; Bibian, M.; Wu, W.; Hernandez, P.; Park, H.; Wu, Y.; Luo, J. L.; LoGrasso, P. V.; Feng, Y. Bis-aryl urea derivatives as potent and selective LIM kinase (Limk) inhibitors. J. Med. Chem. 2015, 58, 1846– 1861, DOI: 10.1021/jm501680m[ACS Full Text], [CAS], Google Scholar320https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVWgtb4%253D&md5=67352d15ab435e75f561552f283b29b9Bis-aryl Urea Derivatives as Potent and Selective LIM Kinase (Limk) InhibitorsYin, Yan; Zheng, Ke; Eid, Nibal; Howard, Shannon; Jeong, Ji-Hak; Yi, Fei; Guo, Jia; Park, Chul Min; Bibian, Mathieu; Wu, Weilin; Hernandez, Pamela; Park, HaJeung; Wu, Yuntao; Luo, Jun-Li; LoGrasso, Philip V.; Feng, YangboJournal of Medicinal Chemistry (2015), 58 (4), 1846-1861CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The discovery/optimization of bis-aryl ureas as Limk inhibitors to obtain high potency and selectivity and appropriate pharmacokinetic properties through systematic SAR studies is reported. Docking studies supported the obsd. SAR. Optimized Limk inhibitors had high biochem. potency (IC50 < 25 nM), excellent selectivity against ROCK and JNK kinases (>400-fold), potent inhibition of cofilin phosphorylation in A7r5, PC-3, and CEM-SS T cells (IC50 < 1 μM), and good in vitro and in vivo pharmacokinetic properties. In the profiling against a panel of 61 kinases, compd. I at 1 μM inhibited only Limk1 and STK16 with ≥80% inhibition. Compds. I and II were highly efficient in inhibiting cell-invasion/migration in PC-3 cells. In addn., compd. III was demonstrated to be effective on reducing intraocular pressure on rat eyes. Taken together, these data demonstrated that the authors had developed a novel class of bis-aryl urea derived potent and selective Limk inhibitors.
- 321Chang, Y.; Lu, X.; Shibu, M. A.; Dai, Y. B.; Luo, J.; Zhang, Y.; Li, Y.; Zhao, P.; Zhang, Z.; Xu, Y.; Tu, Z. C.; Zhang, Q. W.; Yun, C. H.; Huang, C. Y.; Ding, K. Structure based design of N-(3-((1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)benzenesulfonamides as selective Leucine-zipper and Sterile-α motif kinase (ZAK) inhibitors. J. Med. Chem. 2017, 60, 5927– 5932, DOI: 10.1021/acs.jmedchem.7b00572[ACS Full Text], [CAS], Google Scholar321https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXpt1Kntb4%253D&md5=897a22435eaf2f7721813f23eb40a62aStructure Based Design of N-(3-(1H-Pyrazolo[3,4-b]pyridin-5-yl)ethynyl)benzenesulfonamides as Selective Leucine-Zipper and Sterile-α Motif Kinase (ZAK) InhibitorsChang, Yu; Lu, Xiaoyun; Shibu, Marthandam Asokan; Dai, Yi-Bo; Luo, Jinfeng; Zhang, Yan; Li, Yingjun; Zhao, Peng; Zhang, Zhang; Xu, Yong; Tu, Zheng-Chao; Zhang, Qing-Wen; Yun, Cai-Hong; Huang, Chih-Yang; Ding, KeJournal of Medicinal Chemistry (2017), 60 (13), 5927-5932CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of N-(3-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)benzenesulfonamides were designed as the first class of highly selective ZAK inhibitors. The representative compd. I strongly inhibits the kinase activity of ZAK with an IC50 of 3.3 nM and dose-dependently suppresses the activation of ZAK downstream signals in vitro and in vivo, while it is significantly less potent for the majority of 403 nonmutated kinases evaluated. Compd. I also exhibits orally therapeutic effects on cardiac hypertrophy in a spontaneous hypertensive rat model.
- 322Yang, J.; Shibu, M. A.; Kong, L.; Luo, J.; BadrealamKhan, F.; Huang, Y.; Tu, Z. C.; Yun, C. H.; Huang, C. Y.; Ding, K.; Lu, X. Design, synthesis, and structure-activity relationships of 1,2,3-triazole benzenesulfonamides as new selective Leucine-zipper and Sterile-α motif kinase (ZAK) inhibitors. J. Med. Chem. 2020, 63, 2114– 2130, DOI: 10.1021/acs.jmedchem.9b00664[ACS Full Text], [CAS], Google Scholar322https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtV2ltr7P&md5=30adc89c957005c96deb7fdbb871065bDesign, Synthesis, and Structure-Activity Relationships of 1,2,3-Triazole Benzenesulfonamides as New Selective Leucine-Zipper and Sterile-α Motif Kinase (ZAK) InhibitorsYang, Jianzhang; Shibu, Marthandam Asokan; Kong, Lulu; Luo, Jinfeng; BadrealamKhan, Farheen; Huang, Yanhui; Tu, Zheng-Chao; Yun, Cai-Hong; Huang, Chih-Yang; Ding, Ke; Lu, XiaoyunJournal of Medicinal Chemistry (2020), 63 (5), 2114-2130CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)ZAK is a new promising target for discovery of drugs with activity against antihypertrophic cardiomyopathy (HCM). A series of 1,2,3-triazole benzenesulfonamides were designed and synthesized as selective ZAK inhibitors. One of these compds., N-(2,4-Difluoro-3-(4-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-1,2,3-triazol-1-yl)phenyl)-[1,1'-biphenyl]-3-sulfonamide binds tightly to ZAK protein (Kd = 8.0 nM) and potently suppresses the kinase function of ZAK with single-digit nM (IC50 = 4.0 nM) and exhibits excellent selectivity in a KINOMEscan screening platform against a panel of 403 wild-type kinases. This compd. dose dependently blocks p38/GATA-4 and JNK/c-Jun signaling and demonstrates promising in vivo anti-HCM efficacy upon oral administration in a spontaneous hypertensive rat (SHR) model. Compd. N-(2,4-Difluoro-3-(4-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-1,2,3-triazol-1-yl)phenyl)-[1,1'-biphenyl]-3-sulfonamide may serve as a lead compd. for new anti-HCM drug discovery.
- 323Goodfellow, V. S.; Loweth, C. J.; Ravula, S. B.; Wiemann, T.; Nguyen, T.; Xu, Y.; Todd, D. E.; Sheppard, D.; Pollack, S.; Polesskaya, O.; Marker, D. F.; Dewhurst, S.; Gelbard, H. A. Discovery, synthesis, and characterization of an orally bioavailable, brain penetrant inhibitor of mixed lineage kinase 3. J. Med. Chem. 2013, 56, 8032– 8048, DOI: 10.1021/jm401094t[ACS Full Text], [CAS], Google Scholar323https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVGjtrfK&md5=53cb667f098b4de13a3a96b92cd546bfDiscovery, Synthesis, and Characterization of an Orally Bioavailable, Brain Penetrant Inhibitor of Mixed Lineage Kinase 3Goodfellow, Val S.; Loweth, Colin J.; Ravula, Satheesh B.; Wiemann, Torsten; Nguyen, Thong; Xu, Yang; Todd, Daniel E.; Sheppard, David; Pollack, Scott; Polesskaya, Oksana; Marker, Daniel F.; Dewhurst, Stephen; Gelbard, Harris A.Journal of Medicinal Chemistry (2013), 56 (20), 8032-8048CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Inhibition of mixed lineage kinase 3 (MLK3) is a potential strategy for treatment of Parkinson's disease and HIV-1 assocd. neurocognitive disorders (HAND), requiring an inhibitor that can achieve significant brain concn. levels. We report here URMC-099 (1) an orally bioavailable (F = 41%), potent (IC50 = 14 nM) MLK3 inhibitor with excellent brain exposure in mouse PK models and minimal interference with key human CYP450 enzymes or hERG channels. The compd. inhibits LPS-induced TNFα release in microglial cells, HIV-1 Tat-induced release of cytokines in human monocytes and up-regulation of phospho-JNK in Tat-injected brains of mice. Compd. 1 likely functions in HAND preclin. models by inhibiting multiple kinase pathways, including MLK3 and LRRK2 (IC50 = 11 nM). We compare the kinase specificity and BBB penetration of 1 with CEP-1347 (2). Compd. 1 is well tolerated, with excellent in vivo activity in HAND models, and is under investigation for further development.
- 324Zhang, W.; McIver, A. L.; Stashko, M. A.; DeRyckere, D.; Branchford, B. R.; Hunter, D.; Kireev, D.; Miley, M. J.; Norris-Drouin, J.; Stewart, W. M.; Lee, M.; Sather, S.; Zhou, Y.; Di Paola, J. A.; Machius, M.; Janzen, W. P.; Earp, H. S.; Graham, D. K.; Frye, S. V.; Wang, X. Discovery of Mer specific tyrosine kinase inhibitors for the treatment and prevention of thrombosis. J. Med. Chem. 2013, 56, 9693– 9700, DOI: 10.1021/jm4013888[ACS Full Text], [CAS], Google Scholar324https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslOms7rK&md5=07f0b637d009061599c05caaf503372eDiscovery of Mer Specific Tyrosine Kinase Inhibitors for the Treatment and Prevention of ThrombosisZhang, Weihe; McIver, Andrew L.; Stashko, Michael A.; DeRyckere, Deborah; Branchford, Brian R.; Hunter, Debra; Kireev, Dmitri; Miley, Michael J.; Norris-Drouin, Jacqueline; Stewart, Wendy M.; Lee, Minjung; Sather, Susan; Zhou, Yingqiu; Di Paola, Jorge A.; Machius, Mischa; Janzen, William P.; Earp, H. Shelton; Graham, Douglas K.; Frye, Stephen V.; Wang, XiaodongJournal of Medicinal Chemistry (2013), 56 (23), 9693-9700CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The role of Mer kinase in regulating the second phase of platelet activation generates an opportunity to use Mer inhibitors for preventing thrombosis with diminished likelihood for bleeding as compared to current therapies. Toward this end, we have discovered a novel, Mer kinase specific substituted-pyrimidine scaffold using a structure-based drug design and a pseudo ring replacement strategy. The cocrystal structure of Mer with two compds. possessing distinct activity have been detd. Subsequent SAR studies identified compd. I (UNC2881) as a lead compd. for in vivo evaluation. When applied to live cells, I inhibits steady-state Mer kinase phosphorylation with an IC50 value of 22 nM. Treatment with I is also sufficient to block EGF-mediated stimulation of a chimeric receptor contg. the intracellular domain of Mer fused to the extracellular domain of EGFR. In addn., I potently inhibits collagen-induced platelet aggregation, suggesting that this class of inhibitors may have utility for prevention and/or treatment of pathol. thrombosis.
- 325Dow, R. L.; Ammirati, M.; Bagley, S. W.; Bhattacharya, S. K.; Buckbinder, L.; Cortes, C.; El-Kattan, A. F.; Ford, K.; Freeman, G. B.; Guimarães, C. R. W.; Liu, S.; Niosi, M.; Skoura, A.; Tess, D. 2-Aminopyridine-based Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) inhibitors: assessment of mechanism-based safety. J. Med. Chem. 2018, 61, 3114– 3125, DOI: 10.1021/acs.jmedchem.8b00152[ACS Full Text], [CAS], Google Scholar325https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXlvVKnsLg%253D&md5=5ade14664351cabbd0a023b86a5d79972-Aminopyridine-Based Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 (MAP4K4) Inhibitors: Assessment of Mechanism-Based SafetyDow, Robert L.; Ammirati, Mark; Bagley, Scott W.; Bhattacharya, Samit K.; Buckbinder, Leonard; Cortes, Christian; El-Kattan, Ayman F.; Ford, Kristen; Freeman, Gary B.; Guimaraes, Cristiano R. W.; Liu, Shenping; Niosi, Mark; Skoura, Athanasia; Tess, DavidJournal of Medicinal Chemistry (2018), 61 (7), 3114-3125CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Studies have linked the serine-threonine kinase MAP4K4 to the regulation of a no. of biol. processes and/or diseases, including diabetes, cancer, inflammation, and angiogenesis. With a majority of the members of our lead series (e.g., 1) suffering from time-dependent inhibition (TDI) of CYP3A4, we sought design avenues that would eliminate this risk. One such approach arose from the observation that carboxylic acid-based intermediates employed in our discovery efforts retained high MAP4K4 inhibitory potency and were devoid of the TDI risk. The medicinal chem. effort that led to the discovery of this central nervous system-impaired inhibitor together with its preclin. safety profile is described.
- 326Crespo, R. A.; Dang, Q.; Zhou, N. E.; Guthrie, L. M.; Snavely, T. C.; Dong, W.; Loesch, K. A.; Suzuki, T.; You, L.; Wang, W.; O’Malley, T.; Parish, T.; Olsen, D. B.; Sacchettini, J. C. Structure-guided drug design of 6-substituted adenosine analogues as potent inhibitors of mycobacterium tuberculosis adenosine kinase. J. Med. Chem. 2019, 62, 4483– 4499, DOI: 10.1021/acs.jmedchem.9b00020[ACS Full Text], [CAS], Google Scholar326https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXns12isLo%253D&md5=b703c0a70784d4c9d922f12de2224081Structure-Guided Drug Design of 6-Substituted Adenosine Analogues as Potent Inhibitors of Mycobacterium tuberculosis Adenosine KinaseCrespo, Roberto A.; Dang, Qun; Zhou, Nian E.; Guthrie, Liam M.; Snavely, Thomas C.; Dong, Wen; Loesch, Kimberly A.; Suzuki, Takao; You, Lanying; Wang, Wei; O'Malley, Theresa; Parish, Tanya; Olsen, David B.; Sacchettini, James C.Journal of Medicinal Chemistry (2019), 62 (9), 4483-4499CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Mycobacterium tuberculosis adenosine kinase (MtbAdoK) is an essential enzyme of Mtb and forms part of the purine salvage pathway within mycobacteria. Evidence suggests that the purine salvage pathway might play a crucial role in Mtb survival and persistence during its latent phase of infection. In these studies, we adopted a structural approach to the discovery, structure-guided design, and synthesis of a series of adenosine analogs that displayed inhibition consts. ranging from 5 to 120 nM against the enzyme. Two of these compds. exhibited low micromolar activity against Mtb with half maximal effective inhibitory concns. of 1.7 and 4.0 μM. Our selectivity and preliminary pharmacokinetic studies showed that the compds. possess a higher degree of specificity against MtbAdoK when compared with the human counterpart and are well tolerated in rodents, resp. Finally, crystallog. studies showed the mol. basis of inhibition, potency, and selectivity and revealed the presence of a potentially therapeutically relevant cavity unique to the MtbAdoK homodimer.
- 327Song, L.; Merceron, R.; Gracia, B.; Quintana, A. L.; Risseeuw, M. D. P.; Hulpia, F.; Cos, P.; Ainsa, J. A.; Munier-Lehmann, H.; Savvides, S. N.; Van Calenbergh, S. Structure guided lead generation toward Nonchiral M. Tuberculosis thymidylate kinase inhibitors. J. Med. Chem. 2018, 61, 2753– 2775, DOI: 10.1021/acs.jmedchem.7b01570[ACS Full Text], [CAS], Google Scholar327https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjvFWnsr4%253D&md5=c4b195c0bb6969ad71abece65c82bd4aStructure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase InhibitorsSong, Lijun; Merceron, Romain; Gracia, Begona; Quintana, Ainhoa Lucia; Risseeuw, Martijn D. P.; Hulpia, Fabian; Cos, Paul; Ainsa, Jose A.; Munier-Lehmann, Helene; Savvides, Savvas N.; Van Calenbergh, SergeJournal of Medicinal Chemistry (2018), 61 (7), 2753-2775CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)In recent years, thymidylate kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, the authors have built upon the authors' previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK (MtTMPK) inhibitors, and reported here the design of a novel series of non-nucleoside inhibitors of MtTMPK. The inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure-activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, expts. with efflux pump inhibitors and efflux pump knockout mutants were performed. The min. inhibitory concns. of particular inhibitors increased significantly when detd. for the efflux pump mmr knockout mutant, which partly explains the obsd. dissonance.
- 328Sala, M.; Hollinger, K. R.; Thomas, A. G.; Dash, R. P.; Tallon, C.; Veeravalli, V.; Lovell, L.; Kogler, M.; Hrebabecky, H.; Prochazkova, E.; Nesuta, O.; Donoghue, A.; Lam, J.; Rais, R.; Rojas, C.; Slusher, B. S.; Nencka, R. Novel human neutral sphingomyelinase 2 inhibitors as potential therapeutics for Alzheimer’s disease. J. Med. Chem. 2020, 63, 6028– 6056, DOI: 10.1021/acs.jmedchem.0c00278[ACS Full Text], [CAS], Google Scholar328https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXnt12ru7k%253D&md5=ae913fb6068ef7d230f0ef4a49d25975Novel Human Neutral Sphingomyelinase 2 Inhibitors as Potential Therapeutics for Alzheimer's DiseaseSala, Michal; Hollinger, Kristen R.; Thomas, Ajit G.; Dash, Ranjeet P.; Tallon, Carolyn; Veeravalli, Vijayabhaskar; Lovell, Lyndah; Kogler, Martin; Hrebabecky, Hubert; Prochazkova, Eliska; Nesuta, Ondrej; Donoghue, Amanda; Lam, Jenny; Rais, Rana; Rojas, Camilo; Slusher, Barbara S.; Nencka, RadimJournal of Medicinal Chemistry (2020), 63 (11), 6028-6056CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Neutral sphingomyelinase 2 (nSMase2) catalyzes the cleavage of sphingomyelin to phosphorylcholine and ceramide, an essential step in the formation and release of exosomes from cells that is crit. for intracellular communication. Chronic increase of brain nSMase2 activity and related exosome release has been implicated in various pathol. processes, including the progression of Alzheimer's disease (AD), making nSMase2 a viable therapeutic target. Recently, we identified phenyl(R)-(1-(3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b] pyridazin-8-yl) pyrrolidin-3-yl)-carbamate 1 (PDDC)(I), the first nSMase2 inhibitor which possesses both favorable pharmacodynamics and pharmacokinetic (PK) parameters, including substantial oral bioavailability, brain penetration and significant inhibition of exosome release from the brain in vivo. Herein we demonstrate efficacy of 1 (PDDC) in a mouse model of AD and detail extensive structure-activity relationship (SAR) studies with 70 analogs, unveiling several that exert similar or higher activity against nSMase2 with favorable pharmacokinetic properties.
- 329Jimenez, J. M.; Boyall, D.; Brenchley, G.; Collier, P. N.; Davis, C. J.; Fraysse, D.; Keily, S. B.; Henderson, J.; Miller, A.; Pierard, F.; Settimo, L.; Twin, H. C.; Bolton, C. M.; Curnock, A. P.; Chiu, P.; Tanner, A. J.; Young, S. Design and optimization of selective protein kinase C theta (PKCtheta) inhibitors for the treatment of autoimmune diseases. J. Med. Chem. 2013, 56, 1799– 1810, DOI: 10.1021/jm301465a[ACS Full Text], [CAS], Google Scholar329https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXitl2ksb4%253D&md5=6f479112ea9234b9d59e3354da2c11e8Design and Optimization of Selective Protein Kinase C θ (PKCθ) Inhibitors for the Treatment of Autoimmune DiseasesJimenez, Juan-Miguel; Boyall, Dean; Brenchley, Guy; Collier, Philip N.; Davis, Christopher J.; Fraysse, Damien; Keily, Shazia B.; Henderson, Jaclyn; Miller, Andrew; Pierard, Francoise; Settimo, Luca; Twin, Heather C.; Bolton, Claire M.; Curnock, Adam P.; Chiu, Peter; Tanner, Adam J.; Young, StephenJournal of Medicinal Chemistry (2013), 56 (5), 1799-1810CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Protein kinase C θ (PKCθ) has a central role in T cell activation and survival; however, the dependency of T cell responses to the inhibition of this enzyme appears to be dictated by the nature of the antigen and by the inflammatory environment. Studies in PKCθ-deficient mice have demonstrated that while antiviral responses are PKCθ-independent, T cell responses assocd. with autoimmune diseases are PKCθ-dependent. Thus, potent and selective inhibition of PKCθ is expected to block autoimmune T cell responses without compromising antiviral immunity. Herein, we describe the development of potent and selective PKCθ inhibitors, which show exceptional potency in cells and in vivo. By use of a structure based rational design approach, a 1000-fold improvement in potency and 76-fold improvement in selectivity over closely related PKC isoforms such as PKCδ were obtained from the initial HTS hit I, together with a big improvement in lipophilic efficiency (LiPE).
- 330George, D. M.; Breinlinger, E. C.; Argiriadi, M. A.; Zhang, Y.; Wang, J.; Bansal-Pakala, P.; Duignan, D. B.; Honore, P.; Lang, Q.; Mittelstadt, S.; Rundell, L.; Schwartz, A.; Sun, J.; Edmunds, J. J. Optimized protein kinase Ctheta (PKCtheta) inhibitors reveal only modest anti-inflammatory efficacy in a rodent model of arthritis. J. Med. Chem. 2015, 58, 333– 346, DOI: 10.1021/jm5013006[ACS Full Text], [CAS], Google Scholar330https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1Wlu7zM&md5=8737f7f41b661f84117fdca365fc9f9dOptimized Protein Kinase Cθ (PKCθ) Inhibitors Reveal Only Modest Anti-inflammatory Efficacy in a Rodent Model of ArthritisGeorge, Dawn M.; Breinlinger, Eric C.; Argiriadi, Maria A.; Zhang, Yang; Wang, Jianfei; Bansal-Pakala, Pratima; Duignan, David B.; Honore, Prisca; Lang, QingYu; Mittelstadt, Scott; Rundell, Lian; Schwartz, Annette; Sun, Jiakang; Edmunds, Jeremy J.Journal of Medicinal Chemistry (2015), 58 (1), 333-346CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The authors previously demonstrated that selective inhibition of protein kinase Cθ (PKCθ) with a triazinone lead resulted in dose-dependent redn. of paw swelling in a mouse model of arthritis. However, a high concn. was required for efficacy, thus providing only a minimal safety window. Herein the authors describe a strategy to deliver safer compds. based on the hypothesis that optimization of potency in concert with good oral pharmacokinetic (PK) properties would enable in vivo efficacy at reduced exposures, resulting in an improved safety window. Ultimately, transformation of the triazinone lead yielded analogs that demonstrated excellent potency and PK properties and fully inhibited IL-2 prodn. in an acute model. In spite of good exposure, twice-a-day treatment with I in the glucose-6-phosphate isomerase chronic in vivo mouse model of arthritis yielded only moderate efficacy. On the basis of the exposure achieved, the authors conclude that PKCθ inhibition alone is insufficient for complete efficacy in this rodent arthritis model.
- 331Abdel-Halim, M.; Diesel, B.; Kiemer, A. K.; Abadi, A. H.; Hartmann, R. W.; Engel, M. Discovery and optimization of 1,3,5-trisubstituted pyrazolines as potent and highly selective allosteric inhibitors of protein kinase C-zeta. J. Med. Chem. 2014, 57, 6513– 6530, DOI: 10.1021/jm500521n[ACS Full Text], [CAS], Google Scholar331https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht1WmsrzJ&md5=95c3f2c59aabf54afb97632e8bd8ff7cDiscovery and Optimization of 1,3,5-Trisubstituted Pyrazolines as Potent and Highly Selective Allosteric Inhibitors of Protein Kinase C-ζAbdel-Halim, Mohammad; Diesel, Britta; Kiemer, Alexandra K.; Abadi, Ashraf H.; Hartmann, Rolf W.; Engel, MatthiasJournal of Medicinal Chemistry (2014), 57 (15), 6513-6530CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)There is increasing evidence that the atypical protein kinase C, PKCζ, might be a therapeutic target in pulmonary and hepatic inflammatory diseases. However, targeting the highly conserved ATP-binding pocket in the catalytic domain held little promise to achieve selective inhibition. In the present study, the authors introduce 1,3,5-trisubstituted pyrazolines, e.g. I [R1 = 4-HO, 4-F, 4-Cl, etc.; R2 = Me, Ph, t-Bu, etc.; R3 = H, 4-Cl, 4-Br, etc.; R4 = H, Me] as potent and selective allosteric PKCζ inhibitors. The rigid scaffold offered many sites for modification, all acting as hot spots for improving activity, and gave rise to sharp structure-activity relationships. Targeting of PKCζ in cells was confirmed by reporter gene assay, transfection assays, and Western blotting. The strongly reduced cell-free and cellular activities toward a PIF-pocket mutant of PKCζ suggested that the inhibitors most likely bound to the PIF-pocket on the kinase catalytic domain. Thus, using a rigidification strategy and by establishing and optimizing multiple mol. interactions with the binding site, the authors were able to significantly improve the potency of the previously reported PKCζ inhibitors.
- 332Atobe, M.; Serizawa, T.; Yamakawa, N.; Takaba, K.; Nagano, Y.; Yamaura, T.; Tanaka, E.; Tazumi, A.; Bito, S.; Ishiguro, M.; Kawanishi, M. Discovery of 4,6- and 5,7-disubstituted isoquinoline derivatives as a novel class of protein kinase C ζ inhibitors with fragment-merging strategy. J. Med. Chem. 2020, 63, 7143– 7162, DOI: 10.1021/acs.jmedchem.0c00449[ACS Full Text], [CAS], Google Scholar332https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtF2mtL7F&md5=d4c2517567518641c8581643e464b003Discovery of 4,6- and 5,7-Disubstituted Isoquinoline Derivatives as a Novel Class of Protein Kinase C ζ Inhibitors with Fragment-Merging StrategyAtobe, Masakazu; Serizawa, Takayuki; Yamakawa, Natsumi; Takaba, Kenichiro; Nagano, Yukiko; Yamaura, Toshiaki; Tanaka, Eiichi; Tazumi, Atsutoshi; Bito, Shino; Ishiguro, Masashi; Kawanishi, MasashiJournal of Medicinal Chemistry (2020), 63 (13), 7143-7162CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Two chem. series of novel protein kinase C ζ (PKCζ) inhibitors, 4,6-disubstituted and 5,7-disubstituted isoquinolines, were rapidly identified using our fragment merging strategy. This methodol. involves biochem. screening of a high concn. of a monosubstituted isoquinoline fragment library, then merging hit isoquinoline fragments into a single compd. Our strategy can be applied to the discovery of other challenging kinase inhibitors without protein-ligand structural information. Furthermore, our optimization effort identified the highly potent and orally available 5,7-isoquinoline 37(I) from the second chem. series. Compd. 37 showed good efficacy in a mouse collagen-induced arthritis model. The in vivo studies suggest that PKCζ inhibition is a novel target for rheumatoid arthritis (RA) and that 5,7-disubstituted isoquinoline 37 has the potential to elucidate the biol. consequences of PKCζ inhibition, specifically in terms of therapeutic intervention for RA.
- 333Slack-Davis, J. K.; Martin, K. H.; Tilghman, R. W.; Iwanicki, M.; Ung, E. J.; Autry, C.; Luzzio, M. J.; Cooper, B.; Kath, J. C.; Roberts, W. G.; Parsons, J. T. Cellular characterization of a novel focal adhesion kinase inhibitor. J. Biol. Chem. 2007, 282, 14845– 14852, DOI: 10.1074/jbc.M606695200[Crossref], [PubMed], [CAS], Google Scholar333https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXltFemtbY%253D&md5=38e97c67d37fbcbde006e6937ae4e360Cellular Characterization of a Novel Focal Adhesion Kinase InhibitorSlack-Davis, Jill K.; Martin, Karen H.; Tilghman, Robert W.; Iwanicki, Marcin; Ung, Ethan J.; Autry, Christopher; Luzzio, Michael J.; Cooper, Beth; Kath, John C.; Roberts, W. Gregory; Parsons, J. ThomasJournal of Biological Chemistry (2007), 282 (20), 14845-14852CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Focal adhesion kinase (FAK) is a member of a family of non-receptor protein-tyrosine kinases that regulates integrin and growth factor signaling pathways involved in cell migration, proliferation, and survival. FAK expression is increased in many cancers, including breast and prostate cancer. Here we describe perturbation of adhesion-mediated signaling with a FAK inhibitor, PF-573,228. In vitro, this compd. inhibited purified recombinant catalytic fragment of FAK with an IC50 of 4 nM. In cultured cells, PF-573,228 inhibited FAK phosphorylation on Tyr397 with an IC50 of 30-100 nM. Treatment of cells with concns. of PF-573,228 that significantly decreased FAK Tyr397 phosphorylation failed to inhibit cell growth or induce apoptosis. In contrast, treatment with PF-573,228 inhibited both chemotactic and haptotactic migration concomitant with the inhibition of focal adhesion turnover. These studies show that PF-573,228 serves as a useful tool to dissect the functions of FAK in integrin-dependent signaling pathways in normal and cancer cells and forms the basis for the generation of compds. amenable for preclin. and patient trials.
- 334Tso, S. C.; Lou, M.; Wu, C. Y.; Gui, W. J.; Chuang, J. L.; Morlock, L. K.; Williams, N. S.; Wynn, R. M.; Qi, X.; Chuang, D. T. Development of dihydroxyphenyl sulfonylisoindoline derivatives as liver-targeting pyruvate dehydrogenase kinase inhibitors. J. Med. Chem. 2017, 60, 1142– 1150, DOI: 10.1021/acs.jmedchem.6b01540[ACS Full Text], [CAS], Google Scholar334https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVKisrs%253D&md5=70c22064b3920f8ff871e0265818a201Development of Dihydroxyphenyl Sulfonylisoindoline Derivatives as Liver-Targeting Pyruvate Dehydrogenase Kinase InhibitorsTso, Shih-Chia; Lou, Mingliang; Wu, Cheng-Yang; Gui, Wen-Jun; Chuang, Jacinta L.; Morlock, Lorraine K.; Williams, Noelle S.; Wynn, R. Max; Qi, Xiangbing; Chuang, David T.Journal of Medicinal Chemistry (2017), 60 (3), 1142-1150CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Pyruvate dehydrogenase kinases 1-4 (PDK1-4) neg. control activity of the pyruvate dehydrogenase complex (PDC) and are up-regulated in obesity, diabetes, heart failure and cancer. The authors reported earlier two novel pan-PDK inhibitors PS8 [4-((5-hydroxyisoindolin-2-yl)sulfonyl)benzene-1,3-diol] and PS10 [2-((2,4-dihydroxyphenyl)sulfonyl)isoindoline-4,6-diol] that targeted the ATP-binding pocket in PDKs. Here, the authors developed a new generation of PDK inhibitors by extending the dihydroxyphenyl sulfonylisoindoline scaffold in PS8 and PS10 to the entrance region of the ATP-binding pocket in PDK2. The lead inhibitor PS46 [(S)-3-amino-4-(4-((2-((2,4-dihydroxyphenyl)sulfonyl)isoindolin-5-yl)amino)piperidin-1-yl)-4-oxobutanamide] (17) shows a ∼8-fold lower IC50 (58 nM) than 2 (456 nM). In the crystal structure, the asparagine moiety in 17 provides addnl. interactions with Glu 262 from PDK2. Treatment of diet-induced obese mice with 17 resulted in significant liver-specific augmentation of PDC activity, accompanied by improved glucose tolerance and drastically reduced hepatic steatosis. These findings support 17 as a potential glucose-lowering therapeutic targeting liver for obesity and type 2 diabetes.
- 335Lee, D.; Pagire, H. S.; Pagire, S. H.; Bae, E. J.; Dighe, M.; Kim, M.; Lee, K. M.; Jang, Y. K.; Jaladi, A. K.; Jung, K. Y.; Yoo, E. K.; Gim, H. E.; Lee, S.; Choi, W. I.; Chi, Y. I.; Song, J. S.; Bae, M. A.; Jeon, Y. H.; Lee, G. H.; Liu, K. H.; Lee, T.; Park, S.; Jeon, J. H.; Lee, I. K.; Ahn, J. H. Discovery of novel Pyruvate dehydrogenase kinase 4 inhibitors for potential oral treatment of metabolic diseases. J. Med. Chem. 2019, 62, 575– 588, DOI: 10.1021/acs.jmedchem.8b01168[ACS Full Text], [CAS], Google Scholar335https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXkvFakuw%253D%253D&md5=31b365c1d241ac0d121d6a4a7bc13a54Discovery of Novel Pyruvate Dehydrogenase Kinase 4 Inhibitors for Potential Oral Treatment of Metabolic DiseasesLee, Dahye; Pagire, Haushabhau S.; Pagire, Suvarna H.; Bae, Eun Jung; Dighe, Mahesh; Kim, Minhee; Lee, Kyu Myung; Jang, Yoon Kyung; Jaladi, Ashok Kumar; Jung, Kwan-Young; Yoo, Eun Kyung; Gim, Hee Eon; Lee, Seungmi; Choi, Won-Il; Chi, Young-In; Song, Jin Sook; Bae, Myung Ae; Jeon, Yong Hyun; Lee, Ga-Hyun; Liu, Kwang-Hyeon; Lee, Taeho; Park, Sungmi; Jeon, Jae-Han; Lee, In-Kyu; Ahn, Jin HeeJournal of Medicinal Chemistry (2019), 62 (2), 575-588CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Pyruvate dehydrogenase kinase 4 (PDK4) activation is assocd. with metabolic diseases including hyperglycemia, insulin resistance, allergies, and cancer. Structural modifications of hit anthraquinone led to the identification of a new series of allosteric PDK4 inhibitors. Among this series, compd. 8c showed promising in vitro activity with an IC50 value of 84 nM. Good metabolic stability, pharmacokinetic profiles, and possible metabolites were suggested. Compd. 8c improved glucose tolerance in diet-induced obese mice and ameliorated allergic reactions in a passive cutaneous anaphylaxis mouse model. Addnl., compd. 8c exhibited anticancer activity by controlling cell proliferation, transformation, and apoptosis. From the mol. docking studies, compd. 8c displayed optimal fitting in the lipoamide binding site (allosteric) with a full fitness, providing a new scaffold for drug development toward PDK4 inhibitors.
- 336Osgerby, L.; Lai, Y. C.; Thornton, P. J.; Amalfitano, J.; Le Duff, C. S.; Jabeen, I.; Kadri, H.; Miccoli, A.; Tucker, J. H. R.; Muqit, M. M. K.; Mehellou, Y. Kinetin riboside and its protides activate the parkinson’s disease associated PTEN-induced putative kinase 1 (PINK1) independent of mitochondrial depolarization. J. Med. Chem. 2017, 60, 3518– 3524, DOI: 10.1021/acs.jmedchem.6b01897[ACS Full Text], [CAS], Google Scholar336https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXkslKlt7s%253D&md5=bc90c5fa151f4c8e63d4a96a1297bc3aKinetin Riboside and Its ProTides Activate the Parkinson's Disease Associated PTEN-Induced Putative Kinase 1 (PINK1) Independent of Mitochondrial DepolarizationOsgerby, Laura; Lai, Yu-Chiang; Thornton, Peter J.; Amalfitano, Joseph; Le Duff, Cecile S.; Jabeen, Iqra; Kadri, Hachemi; Miccoli, Ageo; Tucker, James H. R.; Muqit, Miratul M. K.; Mehellou, YoucefJournal of Medicinal Chemistry (2017), 60 (8), 3518-3524CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Since loss of function mutations of PINK1 lead to early onset Parkinson's disease, there has been growing interest in the discovery of small mols. that amplify the kinase activity of PINK1. We herein report the design, synthesis, serum stability, and hydrolysis of four kinetin riboside ProTides. These ProTides, along with kinetin riboside, activated PINK1 in cells independent of mitochondrial depolarization. This highlights the potential of modified nucleosides and their phosphate prodrugs as treatments for neurodegenerative diseases.
- 337Meredith, E. L.; Ardayfio, O.; Beattie, K.; Dobler, M. R.; Enyedy, I.; Gaul, C.; Hosagrahara, V.; Jewell, C.; Koch, K.; Lee, W.; Lehmann, H.; McKinsey, T. A.; Miranda, K.; Pagratis, N.; Pancost, M.; Patnaik, A.; Phan, D.; Plato, C.; Qian, M.; Rajaraman, V.; Rao, C.; Rozhitskaya, O.; Ruppen, T.; Shi, J.; Siska, S. J.; Springer, C.; van Eis, M.; Vega, R. B.; von Matt, A.; Yang, L.; Yoon, T.; Zhang, J. H.; Zhu, N.; Monovich, L. G. Identification of orally available naphthyridine protein kinase D inhibitors. J. Med. Chem. 2010, 53, 5400– 5421, DOI: 10.1021/jm100075z[ACS Full Text], [CAS], Google Scholar337https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXovVCitbk%253D&md5=252f56b32d89af3cdda5f970f2f98e74Identification of Orally Available Naphthyridine Protein Kinase D InhibitorsMeredith, Erik L.; Ardayfio, Ophelia; Beattie, Kimberly; Dobler, Markus R.; Enyedy, Istvan; Gaul, Christoph; Hosagrahara, Vinayak; Jewell, Charles; Koch, Keith; Lee, Wendy; Lehmann, Hans Joerg; McKinsey, Timothy A.; Miranda, Karl; Pagratis, Nikos; Pancost, Margaret; Patnaik, Anup; Phan, Dillon; Plato, Craig; Qian, Ming; Rajaraman, Vasumathy; Rao, Chang; Rozhitskaya, Olga; Ruppen, Thomas; Shi, Jie; Siska, Sarah J.; Springer, Clayton; van Eis, Maurice; Vega, Richard B.; von Matt, Anette; Yang, Lihua; Yoon, Taeyoung; Zhang, Ji-Hu; Zhu, Na; Monovich, Lauren G.Journal of Medicinal Chemistry (2010), 53 (15), 5400-5421CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A novel 2,6-naphthyridine was identified by high throughput screen (HTS) as a dual protein kinase C/D (PKC/PKD) inhibitor. PKD inhibition in the heart was proposed as a potential antihypertrophic mechanism with application as a heart failure therapy. As PKC was previously identified as the immediate upstream activator of PKD, PKD vs PKC selectivity was essential to understand the effect of PKD inhibition in models of cardiac hypertrophy and heart failure. The present study describes the modification of the HTS hit to a series of prototype pan-PKD inhibitors with routine 1000-fold PKD vs PKC selectivity. Example compds. inhibited PKD activity in vitro, in cells, and in vivo following oral administration. Their effects on heart morphol. and function are discussed herein.
- 338Vincetti, P.; Caporuscio, F.; Kaptein, S.; Gioiello, A.; Mancino, V.; Suzuki, Y.; Yamamoto, N.; Crespan, E.; Lossani, A.; Maga, G.; Rastelli, G.; Castagnolo, D.; Neyts, J.; Leyssen, P.; Costantino, G.; Radi, M. Discovery of multitarget antivirals acting on both the dengue virus NS5-NS3 interaction and the host src/fyn kinases. J. Med. Chem. 2015, 58, 4964– 4975, DOI: 10.1021/acs.jmedchem.5b00108[ACS Full Text], [CAS], Google Scholar338https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXpsFaksro%253D&md5=43671e087a9f7c8b0735e7dd260eeadbDiscovery of Multitarget Antivirals Acting on Both the Dengue Virus NS5-NS3 Interaction and the Host Src/Fyn KinasesVincetti, Paolo; Caporuscio, Fabiana; Kaptein, Suzanne; Gioiello, Antimo; Mancino, Valentina; Suzuki, Youichi; Yamamoto, Naoki; Crespan, Emmanuele; Lossani, Andrea; Maga, Giovanni; Rastelli, Giulio; Castagnolo, Daniele; Neyts, Johan; Leyssen, Pieter; Costantino, Gabriele; Radi, MarcoJournal of Medicinal Chemistry (2015), 58 (12), 4964-4975CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)This study describes the discovery of novel dengue virus inhibitors targeting both a crucial viral protein-protein interaction and an essential host cell factor as a strategy to reduce the emergence of drug resistance. Starting from known c-Src inhibitors, a virtual screening was performed to identify mols. able to interact with a recently discovered allosteric pocket on the dengue virus NS5 polymerase. The selection of cheap-to-produce scaffolds and the exploration of the biol. relevant chem. space around them suggested promising candidates for chem. synthesis. A series of purines emerged as the most interesting candidates able to inhibit virus replication at low micromolar concns. with no significant toxicity to the host cell. Among the identified antivirals, compd. I proved to be 10 times more potent than ribavirin, showed a better selectivity index and represents the first-in-class DENV-NS5 allosteric inhibitor able to target both the virus NS5-NS3 interaction and the host kinases c-Src/Fyn.
- 339Imamura, K.; Izumi, Y.; Watanabe, A.; Tsukita, K.; Woltjen, K.; Yamamoto, T.; Hotta, A.; Kondo, T.; Kitaoka, S.; Ohta, A.; Tanaka, A.; Watanabe, D.; Morita, M.; Takuma, H.; Tamaoka, A.; Kunath, T.; Wray, S.; Furuya, H.; Era, T.; Makioka, K.; Okamoto, K.; Fujisawa, T.; Nishitoh, H.; Homma, K.; Ichijo, H.; Julien, J. P.; Obata, N.; Hosokawa, M.; Akiyama, H.; Kaneko, S.; Ayaki, T.; Ito, H.; Kaji, R.; Takahashi, R.; Yamanaka, S.; Inoue, H. The Src/c-Abl pathway is a potential therapeutic target in amyotrophic lateral sclerosis. Sci. Transl. Med. 2017, 9, eaaf3962 DOI: 10.1126/scitranslmed.aaf3962
- 340Prado, V.; Lence, E.; Maneiro, M.; Vazquez-Ucha, J. C.; Beceiro, A.; Thompson, P.; Hawkins, A. R.; Gonzalez-Bello, C. Targeting the motion of shikimate kinase: development of competitive inhibitors that stabilize an inactive open conformation of the enzyme. J. Med. Chem. 2016, 59, 5471– 5487, DOI: 10.1021/acs.jmedchem.6b00483[ACS Full Text], [CAS], Google Scholar340https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XnslWiurY%253D&md5=9022076b2c4efd51c65322374dfb7ed7Targeting the Motion of Shikimate Kinase: Development of Competitive Inhibitors that Stabilize an Inactive Open Conformation of the EnzymePrado, Veronica; Lence, Emilio; Maneiro, Maria; Vazquez-Ucha, Juan C.; Beceiro, Alejandro; Thompson, Paul; Hawkins, Alastair R.; Gonzalez-Bello, ConcepcionJournal of Medicinal Chemistry (2016), 59 (11), 5471-5487CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The large conformational changes obsd. by Mol. Dynamics simulation studies on the product release in the LID and shikimic acid binding (SB) domains of the shikimate kinase (SK) enzyme have been exploited in the development of reversible competitive inhibitors against SK from Mycobacterium tuberculosis and Helicobacter pylori. This enzyme is a recognized target for antibiotic drug discovery. The reported C5-substituted shikimic acid analogs interact with the dynamic apolar pocket that surrounds the C4 and C5 hydroxyl groups of the natural substrate, cause the opening of the LID and SB domains, and capture the essential arginine far from the ATP binding site as required for catalysis. The 3-nitrobenzyl 3e and 5-benzothiophenyl derivs. 3i proved to be the most potent inhibitors. An ester prodrug of 3i was the most efficient deriv. in achieving good in vitro activity against H. pylori, having a MIC value of 4 μg/mL.
- 341Mathews, T. P.; Kennedy, A. J.; Kharel, Y.; Kennedy, P. C.; Nicoara, O.; Sunkara, M.; Morris, A. J.; Wamhoff, B. R.; Lynch, K. R.; Macdonald, T. L. Discovery, biological evaluation, and structure-activity relationship of amidine based sphingosine kinase inhibitors. J. Med. Chem. 2010, 53, 2766– 2778, DOI: 10.1021/jm901860h[ACS Full Text], [CAS], Google Scholar341https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXivVajsbw%253D&md5=65dd6f8fe9a0d718b7491a8b919647ebDiscovery, Biological Evaluation, and Structure-Activity Relationship of Amidine Based Sphingosine Kinase InhibitorsMathews, Thomas P.; Kennedy, Andrew J.; Kharel, Yugesh; Kennedy, Perry C.; Nicoara, Oana; Sunkara, Manjula; Morris, Andrew J.; Wamhoff, Brian R.; Lynch, Kevin R.; MacDonald, Timothy L.Journal of Medicinal Chemistry (2010), 53 (7), 2766-2778CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Sphingosine 1-phosphate (S1P), a potent phospholipid growth and trophic factor, is synthesized in vivo by two sphingosine kinases. Thus these kinases have been proposed as important drug targets for treatment of hyperproliferative diseases and inflammation. We report here a new class of amidine-based sphingosine analogs that are competitive inhibitors of sphingosine kinases exhibiting varying degrees of enzyme selectivity. These inhibitors display KI values in the submicromolar range for both sphingosine kinases and, in cultured vascular smooth muscle cells, decrease S1P levels and initiate growth arrest.
- 342Boibessot, T.; Zschiedrich, C. P.; Lebeau, A.; Benimelis, D.; Dunyach-Remy, C.; Lavigne, J. P.; Szurmant, H.; Benfodda, Z.; Meffre, P. The rational design, synthesis, and antimicrobial properties of thiophene derivatives that inhibit bacterial histidine kinases. J. Med. Chem. 2016, 59, 8830– 8847, DOI: 10.1021/acs.jmedchem.6b00580[ACS Full Text], [CAS], Google Scholar342https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVChtrrO&md5=d19c39753e7fab31413fa38a8ebc2be9The Rational Design, Synthesis, and Antimicrobial Properties of Thiophene Derivatives That Inhibit Bacterial Histidine KinasesBoibessot, Thibaut; Zschiedrich, Christopher P.; Lebeau, Alexandre; Benimelis, David; Dunyach-Remy, Catherine; Lavigne, Jean-Philippe; Szurmant, Hendrik; Benfodda, Zohra; Meffre, PatrickJournal of Medicinal Chemistry (2016), 59 (19), 8830-8847CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The emergence of multi-drug-resistant bacteria emphasizes the urgent need for novel antibacterial compds. targeting unique cellular processes. Two-component signal transduction systems (TCSs) are commonly used by bacteria to couple environmental stimuli to adaptive responses, are absent in mammals, and are embedded in various pathogenic pathways. To attenuate these signaling pathways, we aimed to target the TCS signal transducer histidine kinase (HK) by focusing on their highly conserved ATP-binding domain. We used a structure-based drug design strategy that begins from an inhibitor-bound crystal structure and includes a significant no. of structurally simplifying "intuitive" modifications to arrive at the simple achiral, biaryl target structures. Thus, ligands were designed, leading to a series of thiophene derivs. These compds. were synthesized and evaluated in vitro against bacterial HKs. We identified eight compds. with significant inhibitory activities against these proteins, two of which exhibited broad-spectrum antimicrobial activity. The compds. were also evaluated as adjuvants for the treatment of resistant bacteria. One compd. was found to restore the sensitivity of these bacteria to the resp. antibiotics.
- 343Goswami, M.; Wilke, K. E.; Carlson, E. E. Rational design of selective adenine-based scaffolds for inactivation of Bacterial histidine kinases. J. Med. Chem. 2017, 60, 8170– 8182, DOI: 10.1021/acs.jmedchem.7b01066[ACS Full Text], [CAS], Google Scholar343https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFeiurrO&md5=ba1ffc268f101ee0fa08c3f8c3dcd54bRational Design of Selective Adenine-Based Scaffolds for Inactivation of Bacterial Histidine KinasesGoswami, Manibarsha; Wilke, Kaelyn E.; Carlson, Erin E.Journal of Medicinal Chemistry (2017), 60 (19), 8170-8182CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Bacterial histidine kinases (HKs) are quintessential regulatory enzymes found ubiquitously in bacteria. Apart from regulatory roles, they are also involved in the prodn. of virulence factors and conferring resistance to various antibiotics in pathogenic microbes. We have previously reported compds. that inhibit multiple HKs by targeting the conserved catalytic and ATP-binding (CA) domain. Herein, we conduct a detailed structure-activity relationship assessment of adenine-based inhibitors using biochem. and docking methods. These studies have lead to several observations. First, interaction of an inhibitor's amine group with the conserved, active-site Asp is essential for activity and likely dictates its orientation in the binding pocket. Second, a N-NH-N triad in the inhibitor scaffold is highly preferred for binding to conserved Gly:Asp:Asn residues. Lastly, hydrophobic, electron-withdrawing groups at several positions on the adenine core enhance potency. The selectivity of these inhibitors was tested against Heat Shock Protein 90 (HSP90), which possesses a similar ATP-binding fold. We found that groups that target the ATP-lid portion of the catalytic domain, such as a six-membered ring, confer selectivity for HKs.
- 344Martinez-Botella, G.; Breen, J. N.; Duffy, J. E.; Dumas, J.; Geng, B.; Gowers, I. K.; Green, O. M.; Guler, S.; Hentemann, M. F.; Hernandez-Juan, F. A.; Joseph-McCarthy, D.; Kawatkar, S.; Larsen, N. A.; Lazari, O.; Loch, J. T.; Macritchie, J. A.; McKenzie, A. R.; Newman, J. V.; Olivier, N. B.; Otterson, L. G.; Owens, A. P.; Read, J.; Sheppard, D. W.; Keating, T. A. Discovery of selective and potent inhibitors of gram-positive bacterial thymidylate kinase (TMK). J. Med. Chem. 2012, 55, 10010– 10021, DOI: 10.1021/jm3011806[ACS Full Text], [CAS], Google Scholar344https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVOhsL7P&md5=47d16055c461422d98fb0d8afb44dde2Discovery of Selective and Potent Inhibitors of Gram-Positive Bacterial Thymidylate Kinase (TMK)Martinez-Botella, Gabriel; Breen, John N.; Duffy, James E. S.; Dumas, Jacques; Geng, Bolin; Gowers, Ian K.; Green, Oluyinka M.; Guler, Satenig; Hentemann, Martin F.; Hernandez-Juan, Felix A.; Joseph-McCarthy, Diane; Kawatkar, Sameer; Larsen, Nicholas A.; Lazari, Ovadia; Loch, James T.; Macritchie, Jacqueline A.; McKenzie, Andrew R.; Newman, Joseph V.; Olivier, Nelson B.; Otterson, Linda G.; Owens, Andrew P.; Read, Jon; Sheppard, David W.; Keating, Thomas A.Journal of Medicinal Chemistry (2012), 55 (22), 10010-10021CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Thymidylate kinase (TMK) is an essential enzyme in bacterial DNA synthesis. The deoxythymidine monophosphate (dTMP) substrate binding pocket was targeted in a rational-design, structure-supported effort, yielding a unique series of antibacterial agents showing a novel, induced-fit binding mode. Lead optimization, aided by X-ray crystallog., led to picomolar inhibitors of both Streptococcus pneumoniae and Staphylococcus aureus TMK. MICs < 1 μg/mL were achieved against methicillin-resistant S. aureus (MRSA), S. pneumoniae, and vancomycin-resistant Enterococcus (VRE). Log D adjustments yielded single diastereomers 14 (TK-666) and 46, showing a broad antibacterial spectrum against Gram-pos. bacteria and excellent selectivity against the human thymidylate kinase ortholog.
- 345Naik, M.; Raichurkar, A.; Bandodkar, B. S.; Varun, B. V.; Bhat, S.; Kalkhambkar, R.; Murugan, K.; Menon, R.; Bhat, J.; Paul, B.; Iyer, H.; Hussein, S.; Tucker, J. A.; Vogtherr, M.; Embrey, K. J.; McMiken, H.; Prasad, S.; Gill, A.; Ugarkar, B. G.; Venkatraman, J.; Read, J.; Panda, M. Structure guided lead generation for M. tuberculosis thymidylate kinase (Mtb TMK): discovery of 3-cyanopyridone and 1,6-naphthyridin-2-one as potent inhibitors. J. Med. Chem. 2015, 58, 753– 766, DOI: 10.1021/jm5012947[ACS Full Text], [CAS], Google Scholar345https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVCku7jN&md5=3a9ec4e7eea4e656b12776f91091cebbStructure Guided Lead Generation for M. tuberculosis Thymidylate Kinase (Mtb TMK): Discovery of 3-Cyanopyridone and 1,6-Naphthyridin-2-one as Potent InhibitorsNaik, Maruti; Raichurkar, Anandkumar; Bandodkar, Balachandra S.; Varun, Begur V.; Bhat, Shantika; Kalkhambkar, Rajesh; Murugan, Kannan; Menon, Rani; Bhat, Jyothi; Paul, Beena; Iyer, Harini; Hussein, Syeed; Tucker, Julie A.; Vogtherr, Martin; Embrey, Kevin J.; McMiken, Helen; Prasad, Swati; Gill, Adrian; Ugarkar, Bheemarao G.; Venkatraman, Janani; Read, Jon; Panda, ManoranjanJournal of Medicinal Chemistry (2015), 58 (2), 753-766CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)M. tuberculosis thymidylate kinase (Mtb TMK) has been shown in vitro to be an essential enzyme in DNA synthesis. In order to identify novel leads for Mtb TMK, the authors performed a high throughput biochem. screen and an NMR based fragment screen through which the authors discovered two novel classes of inhibitors, 3-cyanopyridones and 1,6-naphthyridin-2-ones, resp. The authors describe three cyanopyridone subseries that arose during the hit to lead campaign, along with cocrystal structures of representatives with Mtb TMK. Structure aided optimization of the cyanopyridones led to single digit nanomolar inhibitors of Mtb TMK. Fragment based lead generation, augmented by crystal structures and the SAR from the cyanopyridones, enabled us to drive the potency of the 1,6-naphthyridin-2-one fragment hit from 500 μM to 200 nM while simultaneously improving the ligand efficiency. Cyanopyridone derivs. contg. sulfoxides and sulfones, e.g. I, showed cellular activity against M. tuberculosis. To the best of the knowledge, these compds. are the first reports of nonthymidine-like inhibitors of Mtb TMK.
- 346Philp, J.; Lawhorn, B. G.; Graves, A. P.; Shewchuk, L.; Rivera, K. L.; Jolivette, L. J.; Holt, D. A.; Gatto, G. J., Jr; Kallander, L. S. 4,6-Diaminopyrimidines as highly preferred Troponin I-interacting kinase (TNNI3K) inhibitors. J. Med. Chem. 2018, 61, 3076– 3088, DOI: 10.1021/acs.jmedchem.8b00125[ACS Full Text], [CAS], Google Scholar346https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXltFCjsro%253D&md5=b3c93adce5f2f02e6b4a805e579d2e744,6-Diaminopyrimidines as Highly Preferred Troponin I-Interacting Kinase (TNNI3K) InhibitorsPhilp, Joanne; Lawhorn, Brian G.; Graves, Alan P.; Shewchuk, Lisa; Rivera, Katrina L.; Jolivette, Larry J.; Holt, Dennis A.; Gatto, Gregory J.; Kallander, Lara S.Journal of Medicinal Chemistry (2018), 61 (7), 3076-3088CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Structure-guided progression of a purine-derived series of TNNI3K inhibitors directed design efforts that produced a novel series of 4,6-diaminopyrimidine inhibitors, an emerging kinase binding motif. Herein, the authors report a detailed understanding of the intrinsic conformational preferences of the scaffold, which impart high specificity for TNNI3K. Further manipulation of the template based on the conformational anal. and addnl. structure-activity relationship studies provided enhancements in kinase selectivity and pharmacokinetics that furnished an advanced series of potent inhibitors. The optimized compds. (e.g., GSK854) are suitable leads for identifying new cardiac medicines and have been employed as in vivo tools in investigational studies aimed at defining the role of TNNI3K within heart failure.
- 347Lawhorn, B. G.; Philp, J.; Zhao, Y.; Louer, C.; Hammond, M.; Cheung, M.; Fries, H.; Graves, A. P.; Shewchuk, L.; Wang, L.; Cottom, J. E.; Qi, H.; Zhao, H.; Totoritis, R.; Zhang, G.; Schwartz, B.; Li, H.; Sweitzer, S.; Holt, D. A.; Gatto, G. J., Jr; Kallander, L. S. Identification of purines and 7-deazapurines as potent and selective type I inhibitors of Troponin I-interacting kinase (TNNI3K). J. Med. Chem. 2015, 58, 7431– 7448, DOI: 10.1021/acs.jmedchem.5b00931[ACS Full Text], [CAS], Google Scholar347https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVygs7rN&md5=d4a66f1ee1b5d62a5443225aca9bcb12Identification of Purines and 7-Deazapurines as Potent and Selective Type I Inhibitors of Troponin I-Interacting Kinase (TNNI3K)Lawhorn, Brian G.; Philp, Joanne; Zhao, Yongdong; Louer, Christopher; Hammond, Marlys; Cheung, Mui; Fries, Harvey; Graves, Alan P.; Shewchuk, Lisa; Wang, Liping; Cottom, Joshua E.; Qi, Hongwei; Zhao, Huizhen; Totoritis, Rachel; Zhang, Guofeng; Schwartz, Benjamin; Li, Hu; Sweitzer, Sharon; Holt, Dennis A.; Gatto, Gregory J., Jr.; Kallander, Lara S.Journal of Medicinal Chemistry (2015), 58 (18), 7431-7448CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of cardiac troponin I-interacting kinase (TNNI3K) inhibitors arising from 3-((9H-purin-6-yl)amino)-N-methyl-benzenesulfonamide (1) is disclosed along with fundamental structure-function relationships that delineate the role of each element of 1 for TNNI3K recognition. An X-ray structure of 1 bound to TNNI3K confirmed its Type I binding mode and is used to rationalize the structure-activity relationship and employed to design potent, selective, and orally bioavailable TNNI3K inhibitors. Identification of the 7-deazapurine heterocycle as a superior template (vs purine) and its elaboration by introduction of C4-benzenesulfonamide and C7- and C8-7-deazapurine substituents produced compds. with substantial improvements in potency (>1000-fold), general kinase selectivity (10-fold improvement), and pharmacokinetic properties (>10-fold increase in poDNAUC). Optimal members of the series have properties suitable for use in in vitro and in vivo expts. aimed at elucidating the role of TNNI3K in cardiac biol. and serve as leads for developing novel heart failure medicines.
- 348Tear, W. F.; Bag, S.; Diaz-Gonzalez, R.; Ceballos-Perez, G.; Rojas-Barros, D. I.; Cordon-Obras, C.; Perez-Moreno, G.; Garcia-Hernandez, R.; Martinez-Martinez, M. S.; Ruiz-Perez, L. M.; Gamarro, F.; Gonzalez Pacanowska, D.; Caffrey, C. R.; Ferrins, L.; Manzano, P.; Navarro, M.; Pollastri, M. P. Selectivity and physicochemical optimization of repurposed pyrazolo[1,5-b]pyridazines for the treatment of human african trypanosomiasis. J. Med. Chem. 2020, 63, 756– 783, DOI: 10.1021/acs.jmedchem.9b01741[ACS Full Text], [CAS], Google Scholar348https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisVWqsLnJ&md5=a214fe962c7e0b38f45b27eedb37fe2aSelectivity and Physicochemical Optimization of Repurposed Pyrazolo[1,5-b]pyridazines for the Treatment of Human African TrypanosomiasisTear, Westley F.; Bag, Seema; Diaz-Gonzalez, Rosario; Ceballos-Perez, Gloria; Rojas-Barros, Domingo I.; Cordon-Obras, Carlos; Perez-Moreno, Guiomar; Garcia-Hernandez, Raquel; Martinez-Martinez, Maria Santos; Ruiz-Perez, Luis Miguel; Gamarro, Francisco; Gonzalez Pacanowska, Dolores; Caffrey, Conor R.; Ferrins, Lori; Manzano, Pilar; Navarro, Miguel; Pollastri, Michael P.Journal of Medicinal Chemistry (2020), 63 (2), 756-783CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)From a high-throughput screen of 42 444 known human kinases inhibitors, a pyrazolo[1,5-b]pyridazine scaffold was identified to begin optimization for the treatment of human African trypanosomiasis. Previously reported data for analogous compds. against human kinases GSK-3β, CDK-2, and CDK-4 were leveraged to try to improve the selectivity of the series, resulting in 23a which showed selectivity for T. b. brucei over these three human enzymes. In parallel, properties known to influence the absorption, distribution, metab., and excretion (ADME) profile of the series were optimized resulting in 20g being progressed into an efficacy study in mice. Though 20g showed toxicity in mice, it also demonstrated CNS penetration in a PK study and significant redn. of parasitemia in four out of the six mice.
- 349Dubreuil, P.; Letard, S.; Ciufolini, M.; Gros, L.; Humbert, M.; Casteran, N.; Borge, L.; Hajem, B.; Lermet, A.; Sippl, W.; Voisset, E.; Arock, M.; Auclair, C.; Leventhal, P. S.; Mansfield, C. D.; Moussy, A.; Hermine, O. Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. PLoS One 2009, 4, e7258 DOI: 10.1371/journal.pone.0007258
- 350Ouyang, L.; Zhang, L.; Zhang, S.; Yao, D.; Zhao, Y.; Wang, G.; Fu, L.; Lei, P.; Liu, B. Small-molecule activator of unc-51-like kinase 1 (ULK1) that induces cytoprotective autophagy for parkinson’s disease treatment. J. Med. Chem. 2018, 61, 2776– 2792, DOI: 10.1021/acs.jmedchem.7b01575[ACS Full Text], [CAS], Google Scholar350https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXlt1Kktr8%253D&md5=f9076a7c130d27308c61632311e6169fSmall-Molecule Activator of UNC-51-Like Kinase 1 (ULK1) That Induces Cytoprotective Autophagy for Parkinson's Disease TreatmentOuyang, Liang; Zhang, Lan; Zhang, Shouyue; Yao, Dahong; Zhao, Yuqian; Wang, Guan; Fu, Leilei; Lei, Peng; Liu, BoJournal of Medicinal Chemistry (2018), 61 (7), 2776-2792CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)UNC-51-like kinase 1 (ULK1), the yeast Atg1 ortholog, is the sole serine-threonine kinase and initiating enzyme in autophagy, which may be regarded as a target in Parkinson's disease (PD). Herein, the authors discovered a small mol. 33i (BL-918, ((R)-2-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-N-(2,4-difluorophenyl)-2-phenylacetamide)) as a potent activator of ULK1 by structure-based drug design. Subsequently, some key amino acid residues (Arg 18, Lys 50, Asn 86, and Tyr 89) were found to be crucial to the binding pocket between ULK1 and 33i by site-directed mutagenesis. Moreover, the authors found that 33i induced autophagy via the ULK complex in SH-SY5Y cells. Intriguingly, this activator displayed a cytoprotective effect on MPP+-treated SH-SY5Y cells, as well as protected against MPTP-induced motor dysfunction and loss of dopaminergic neurons by targeting ULK1-modulated autophagy in mouse models of PD. Together, these results demonstrate the therapeutic potential to target ULK1, and 33i, the novel activator of ULK1, may serve as a candidate drug for future PD treatment.
- 351Meredith, E. L.; Mainolfi, N.; Poor, S.; Qiu, Y.; Miranda, K.; Powers, J.; Liu, D.; Ma, F.; Solovay, C.; Rao, C.; Johnson, L.; Ji, N.; Artman, G.; Hardegger, L.; Hanks, S.; Shen, S.; Woolfenden, A.; Fassbender, E.; Sivak, J. M.; Zhang, Y.; Long, D.; Cepeda, R.; Liu, F.; Hosagrahara, V. P.; Lee, W.; Tarsa, P.; Anderson, K.; Elliott, J.; Jaffee, B. Discovery of oral VEGFR-2 inhibitors with prolonged ocular retention that are efficacious in models of wet age-related macular degeneration. J. Med. Chem. 2015, 58, 9273– 9286, DOI: 10.1021/acs.jmedchem.5b01227[ACS Full Text], [CAS], Google Scholar351https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVehs7fF&md5=11ee9095e9eb62c548dec995a9c369ddDiscovery of Oral VEGFR-2 Inhibitors with Prolonged Ocular Retention That Are Efficacious in Models of Wet Age-Related Macular DegenerationMeredith, Erik L.; Mainolfi, Nello; Poor, Stephen; Qiu, Yubin; Miranda, Karl; Powers, James; Liu, Donglei; Ma, Fupeng; Solovay, Catherine; Rao, Chang; Johnson, Leland; Ji, Nan; Artman, Gerald; Hardegger, Leo; Hanks, Shawn; Shen, Siyuan; Woolfenden, Amber; Fassbender, Elizabeth; Sivak, Jeremy M.; Zhang, Yiqin; Long, Debby; Cepeda, Rosemarie; Liu, Fang; Hosagrahara, Vinayak P.; Lee, Wendy; Tarsa, Peter; Anderson, Karen; Elliott, Jason; Jaffee, BruceJournal of Medicinal Chemistry (2015), 58 (23), 9273-9286CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The benefit of intravitreal anti-VEGF therapy in treating wet age-related macular degeneration (AMD) is well established. Identification of VEGFR-2 inhibitors with optimal ADME properties for an ocular indication provides opportunities for dosing routes beyond intravitreal injection. The authors employed a high-throughput in vivo screening strategy with rodent models of choroidal neovascularization and iterative compd. design to identify VEGFR-2 inhibitors with potential to benefit wet AMD patients. These compds., e.g. I, demonstrate preferential ocular tissue distribution and efficacy after oral administration while minimizing systemic exposure.
- 352Adams, C. M.; Anderson, K.; Artman, G., 3rd; Bizec, J. C.; Cepeda, R.; Elliott, J.; Fassbender, E.; Ghosh, M.; Hanks, S.; Hardegger, L. A.; Hosagrahara, V. P.; Jaffee, B.; Jendza, K.; Ji, N.; Johnson, L.; Lee, W.; Liu, D.; Liu, F.; Long, D.; Ma, F.; Mainolfi, N.; Meredith, E. L.; Miranda, K.; Peng, Y.; Poor, S.; Powers, J.; Qiu, Y.; Rao, C.; Shen, S.; Sivak, J. M.; Solovay, C.; Tarsa, P.; Woolfenden, A.; Zhang, C.; Zhang, Y. The discovery of N-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-((6- ((methylamino)methyl)pyrimidin-4-yl)oxy)-1H-indole-1-carboxamide (Acrizanib), a VEGFR-2 inhibitor specifically designed for topical ocular delivery, as a therapy for neovascular age-related macular degeneration. J. Med. Chem. 2018, 61, 1622– 1635, DOI: 10.1021/acs.jmedchem.7b01731[ACS Full Text], [CAS], Google Scholar352https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitFSjsLg%253D&md5=21b5661580dda231c590bc7505e7be0eThe Discovery of N-(1-Methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-((6- ((methylamino)methyl)pyrimidin-4-yl)oxy)-1H-indole-1-carboxamide (Acrizanib), a VEGFR-2 Inhibitor Specifically Designed for Topical Ocular Delivery, as a Therapy for Neovascular Age-Related Macular DegenerationAdams, Christopher M.; Anderson, Karen; Artman, Gerald; Bizec, Jean-Claude; Cepeda, Rosemarie; Elliott, Jason; Fassbender, Elizabeth; Ghosh, Malay; Hanks, Shawn; Hardegger, Leo A.; Hosagrahara, Vinayak P.; Jaffee, Bruce; Jendza, Keith; Ji, Nan; Johnson, Leland; Lee, Wendy; Liu, Donglei; Liu, Fang; Long, Debby; Ma, Fupeng; Mainolfi, Nello; Meredith, Erik L.; Miranda, Karl; Peng, Yao; Poor, Stephen; Powers, James; Qiu, Yubin; Rao, Chang; Shen, Siyuan; Sivak, Jeremy M.; Solovay, Catherine; Tarsa, Peter; Woolfenden, Amber; Zhang, Chun; Zhang, YiqinJournal of Medicinal Chemistry (2018), 61 (4), 1622-1635CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A noninvasive topical ocular therapy for the treatment of neovascular or "wet" age-related macular degeneration would provide a patient administered alternative to the current std. of care, which requires physician administered intravitreal injections. This manuscript describes a novel strategy for the use of in vivo models of choroidal neovascularization (CNV) as the primary means of developing SAR related to efficacy from topical administration. Ultimately, this effort led to the discovery of acrizanib (LHA510), a small-mol. VEGFR-2 inhibitor with potency and efficacy in rodent CNV models, limited systemic exposure after topical ocular administration, multiple formulation options, and an acceptable rabbit ocular PK profile.
- 353Yamada, K.; Levell, J.; Yoon, T.; Kohls, D.; Yowe, D.; Rigel, D. F.; Imase, H.; Yuan, J.; Yasoshima, K.; DiPetrillo, K.; Monovich, L.; Xu, L.; Zhu, M.; Kato, M.; Jain, M.; Idamakanti, N.; Taslimi, P.; Kawanami, T.; Argikar, U. A.; Kunjathoor, V.; Xie, X.; Yagi, Y. I.; Iwaki, Y.; Robinson, Z.; Park, H. M. Optimization of allosteric With-no-lysine (WNK) kinase inhibitors and efficacy in rodent hypertension models. J. Med. Chem. 2017, 60, 7099– 7107, DOI: 10.1021/acs.jmedchem.7b00708[ACS Full Text], [CAS], Google Scholar353https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1KgtLzF&md5=70c1888c78cf9df946ca48b1887982f9Optimization of Allosteric With-No-Lysine (WNK) Kinase Inhibitors and Efficacy in Rodent Hypertension ModelsYamada, Ken; Levell, Julian; Yoon, Taeyong; Kohls, Darcy; Yowe, David; Rigel, Dean F.; Imase, Hidetomo; Yuan, Jun; Yasoshima, Kayo; DiPetrillo, Keith; Monovich, Lauren; Xu, Lingfei; Zhu, Meicheng; Kato, Mitsunori; Jain, Monish; Idamakanti, Neeraja; Taslimi, Paul; Kawanami, Toshio; Argikar, Upendra A.; Kunjathoor, Vidya; Xie, Xiaoling; Yagi, Yukiko I.; Iwaki, Yuki; Robinson, Zachary; Park, Hyi-ManJournal of Medicinal Chemistry (2017), 60 (16), 7099-7107CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The obsd. structure-activity relationship (SAR) of three distinct ATP noncompetitive With-No-Lysine (WNK) kinase inhibitor series, together with a crystal structure of a previously disclosed allosteric inhibitor bound to WNK1, led to an overlay hypothesis defining core and side-chain relationships across the different series. This in turn enabled an efficient optimization through scaffold morphing, resulting in compds. with a good balance of selectivity, cellular potency and pharmacokinetic profile, which were suitable for in vivo proof-of-concept studies. When dosed orally, the optimized compd. reduced blood pressure in mice overexpressing human WNK1 and in spontaneously hypertensive rats (SHR), and induced diuresis, natriuresis, kaliuresis and blood pressure in SHR, confirming that this mechanism of inhibition of WNK kinase activity is effective at regulating cardiovascular homeostasis.
- 354Pietri, M.; Dakowski, C.; Hannaoui, S.; Alleaume-Butaux, A.; Hernandez-Rapp, J.; Ragagnin, A.; Mouillet-Richard, S.; Haik, S.; Bailly, Y.; Peyrin, J. M.; Launay, J. M.; Kellermann, O.; Schneider, B. PDK1 decreases TACE-mediated α-secretase activity and promotes disease progression in prion and Alzheimer’s diseases. Nat. Med. 2013, 19, 1124– 1131, DOI: 10.1038/nm.3302[Crossref], [PubMed], [CAS], Google Scholar354https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1yltrjP&md5=4292823b5977c5f0d241d95f55b1e87dPDK1 decreases TACE-mediated α-secretase activity and promotes disease progression in prion and Alzheimer's diseasesPietri, Mathea; Dakowski, Caroline; Hannaoui, Samia; Alleaume-Butaux, Aurelie; Hernandez-Rapp, Julia; Ragagnin, Audrey; Mouillet-Richard, Sophie; Haik, Stephane; Bailly, Yannick; Peyrin, Jean-Michel; Launay, Jean-Marie; Kellermann, Odile; Schneider, BenoitNature Medicine (New York, NY, United States) (2013), 19 (9), 1124-1131CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)α-Secretase-mediated cleavage of amyloid precursor protein (APP) precludes formation of neurotoxic amyloid-β (Aβ) peptides, and α-cleavage of cellular prion protein (PrPC) prevents its conversion into misfolded, pathogenic prions (PrPSc). The mechanisms leading to decreased α-secretase activity in Alzheimer's and prion disease remain unclear. Here, we find that tumor necrosis factor-α-converting enzyme (TACE)-mediated α-secretase activity is impaired at the surface of neurons infected with PrPSc or isolated from APP-transgenic mice with amyloid pathol. 3-phosphoinositide-dependent kinase-1 (PDK1) activity is increased in neurons infected with prions or affected by Aβ deposition and in the brains of individuals with Alzheimer's disease. PDK1 induces phosphorylation and caveolin-1-mediated internalization of TACE. This dysregulation of TACE increases PrPSc and Aβ accumulation and reduces shedding of TNF-α receptor type 1 (TNFR1). Inhibition of PDK1 promotes localization of TACE to the plasma membrane, restores TACE-dependent α-secretase activity and cleavage of APP, PrPC and TNFR1, and attenuates PrPSc- and Aβ-induced neurotoxicity. In mice, inhibition or siRNA-mediated silencing of PDK1 extends survival and reduces motor impairment following PrPSc infection and in APP-transgenic mice reduces Alzheimer's disease-like pathol. and memory impairment.
- 355Coffey, G.; Betz, A.; DeGuzman, F.; Pak, Y.; Inagaki, M.; Baker, D. C.; Hollenbach, S. J.; Pandey, A.; Sinha, U. The novel kinase inhibitor PRT062070 (Cerdulatinib) demonstrates efficacy in models of autoimmunity and B-cell cancer. J. Pharmacol. Exp. Ther. 2014, 351, 538– 548, DOI: 10.1124/jpet.114.218164[Crossref], [PubMed], [CAS], Google Scholar355https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvFyhsbbF&md5=caed39628d643e4087ba88f7eaa51326The novel kinase inhibitor PRT062070 (Cerdulatinib) demonstrates efficacy in models of autoimmunity and B-cell cancerCoffey, Greg; Betz, Andreas; DeGuzman, Francis; Pak, Yvonne; Inagaki, Mayuko; Baker, Dale C.; Hollenbach, Stanley J.; Pandey, Anjali; Sinha, UmaJournal of Pharmacology and Experimental Therapeutics (2014), 351 (3), 538-548, 11 pp.CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)The heterogeneity and severity of certain autoimmune diseases and B-cell malignancies warrant simultaneous targeting of multiple disease-relevant signaling pathways. Dual inhibition of spleen tyrosine kinase (SYK) and Janus kinase (JAK) represents such a strategy and may elicit several benefits relative to selective kinase inhibition, such as gaining control over a broader array of disease etiologies, reducing probability of selection for bypass disease mechanisms, and the potential that an overall lower level suppression of individual targets may be sufficient to modulate disease activity. To this end, we provide data on the discovery and preclin. development of PRT062070 [4-(cyclopropylamino)-2-({4-[4-(ethylsulfonyl)piperazin-1-yl]phenyl}amino)pyrimidine-5-carboxamide hydrochloride], an orally active kinase inhibitor that demonstrates activity against SYK and JAK. Cellular assays demonstrated specific inhibitory activity against signaling pathways that use SYK and JAK1/3. Limited inhibition of JAK2 was obsd., and PRT062070 did not inhibit phorbol 12-myristate 13-acetate-mediated signaling or activation in B and T cells nor T-cell antigen receptor-mediated signaling in T cells, providing evidence for selectivity of action. Potent antitumor activity was obsd. in a subset of B-cell lymphoma cell lines. After oral dosing, PRT062070 suppressed inflammation and autoantibody generation in a rat collagen-induced arthritis model and blocked B-cell activation and splenomegaly in a mouse model of chronic B-cell antigen receptor stimulation. PRT062070 is currently under evaluation in a phase I dose escalation study in patients with B-cell leukemia and lymphoma (NCT01994382), with proof-of-concept studies in humans planned to assess therapeutic potential in autoimmune and malignant diseases.
- 356Smyth, L. A.; Collins, I. Measuring and interpreting the selectivity of protein kinase inhibitors. J. Chem. Biol. 2009, 2, 131– 151, DOI: 10.1007/s12154-009-0023-9[Crossref], [PubMed], [CAS], Google Scholar356https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MrkslGqtA%253D%253D&md5=f78ff1202a949a71ffd65e804298c37fMeasuring and interpreting the selectivity of protein kinase inhibitorsSmyth Lynette A; Collins IanJournal of chemical biology (2009), 2 (3), 131-51 ISSN:1864-6158.Protein kinase inhibitors are a well-established class of clinically useful drugs, particularly for the treatment of cancer. Achieving inhibitor selectivity for particular protein kinases often remains a significant challenge in the development of new small molecules as drugs or as tools for chemical biology research. This review summarises the methodologies available for measuring kinase inhibitor selectivity, both in vitro and in cells. The interpretation of kinase inhibitor selectivity data is discussed, particularly with reference to the structural biology of the protein targets. Measurement and prediction of kinase inhibitor selectivity will be important for the development of new multi-targeted kinase inhibitors.
- 357Panicker, R. C.; Chattopadhaya, S.; Coyne, A. G.; Srinivasan, R. Allosteric small-molecule serine/threonine kinase inhibitors. Adv. Exp. Med. Biol. 2019, 1163, 253– 278, DOI: 10.1007/978-981-13-8719-7_11[Crossref], [PubMed], [CAS], Google Scholar357https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXosFeht7Y%253D&md5=aff162e9dee91f765c95fadb2ed7c487Allosteric Small-Molecule Serine/Threonine Kinase InhibitorsPanicker, Resmi C.; Chattopadhaya, Souvik; Coyne, Anthony G.; Srinivasan, RajavelAdvances in Experimental Medicine and Biology (2019), 1163 (Protein Allostery in Drug Discovery), 253-278CODEN: AEMBAP; ISSN:2214-8019. (Springer)A review. Deregulation of protein kinase activity has been linked to many diseases ranging from cancer to AIDS and neurodegenerative diseases. Not surprisingly, drugging the human kinome - the complete set of kinases encoded by the human genome - has been one of the major drug discovery pipelines. Majority of the approved clin. kinase inhibitors target the ATP binding site of kinases. However, the remarkable sequence and structural similarity of ATP binding pockets of kinases make selective inhibition of kinases a daunting task. To circumvent these issues, allosteric inhibitors that target sites other than the orthosteric ATP binding pocket have been developed. The structural diversity of the allosteric sites allows these inhibitors to have higher selectivity, lower toxicity and improved physiochem. properties and overcome drug resistance assocd. with the use of conventional kinase inhibitors. In this chapter, we will focus on the allosteric inhibitors of selected serine/threonine kinases, outline the benefits of using these inhibitors and discuss the challenges and future opportunities.
- 358Wu, P.; Clausen, M. H.; Nielsen, T. E. Allosteric small-molecule kinase inhibitors. Pharmacol. Ther. 2015, 156, 59– 68, DOI: 10.1016/j.pharmthera.2015.10.002[Crossref], [PubMed], [CAS], Google Scholar358https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs12qsb3N&md5=26e4658d325b8f016be29df27bf69ec2Allosteric small-molecule kinase inhibitorsWu, Peng; Clausen, Mads H.; Nielsen, Thomas E.Pharmacology & Therapeutics (2015), 156 (), 59-68CODEN: PHTHDT; ISSN:0163-7258. (Elsevier)Small-mol. kinase inhibitors are invaluable targeted therapeutics for the treatment of various human diseases, esp. cancers. While the majority of approved and developed preclin. small-mol. inhibitors are characterized as type I or type II inhibitors that target the ATP-binding pocket of kinases, the remarkable sequential and structural similarity among ATP pockets renders the selective inhibition of kinases a daunting challenge. Therefore, targeting allosteric pockets of kinases outside the highly conversed ATP pocket has been proposed as a promising alternative to overcome current barriers of kinase inhibitors, including poor selectivity and emergence of drug resistance. In spite of the small no. of identified allosteric inhibitors in comparison with that of inhibitors targeting the ATP pocket, encouraging results, such as the FDA-approval of the first small-mol. allosteric inhibitor trametinib in 2013, the progress of more than 10 other allosteric inhibitors in clin. trials, and the emergence of a pipeline of highly selective and potent preclin. mols., have been reported in the past decade. In this article, we present the current knowledge on allosteric inhibition in terms of conception, classification, potential advantages, and summarized debatable topics in the field. Recent progress and allosteric inhibitors that were identified in the past three years are highlighted in this paper.
- 359Groppe, J. C. Induced degradation of protein kinases by bifunctional small molecules: a next-generation strategy. Expert Opin. Drug Discovery 2019, 14, 1237– 1253, DOI: 10.1080/17460441.2019.1660641[Crossref], [PubMed], [CAS], Google Scholar359https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhslOltLzF&md5=1722b0f3b5d81952abeae40962a62ca6Induced degradation of protein kinases by bifunctional small molecules: a next-generation strategyGroppe, Jay C.Expert Opinion on Drug Discovery (2019), 14 (12), 1237-1253CODEN: EODDBX; ISSN:1746-0441. (Taylor & Francis Ltd.)A review. Protein kinases are a major target for small-mol. drug development. However, relatively few compds. are free of off-target toxicity and reach the clinic. Because the 500-plus kinases share conserved ATP-binding clefts, the site targeted by competitive inhibitors, generation of specific therapeutics remains a nearly intractable challenge. Inducing degrdn., instead of inhibition by occupancy-driven drugs, is an emerging strategy that offers the long-sought specificity, as well as mechanistic benefits. Currently approved inhibitors require steady-state binding and leave proteins intact for interactions in multi-protein complexes. After a general background about induced protein degrdn., perspectives on protein kinases are provided. Induced degrdn. by state-of-the-art compds. (proteolysis-targeting chimeras, PROTACs) has been shown for protein kinases, albeit in early pre-clin. stages. Further work is required to expand the no. of enzymes that could be exploited to direct proteins for degrdn. by ubiquitylation. In addn., despite the simple modularity of the chimeras, generation of hits will require empirical approaches due to the role of protein-protein interactions and distribution of tagging sites. However, given the advantages of degrdn., drug discovery efforts targeting protein kinases should increasingly shift toward generation and screening of inducers of degrdn. and away from occupancy-based inhibitors of old.
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Abstract
Figure 1
Figure 1. SMKIs approved by the U.S. FDA. The INNs of drugs (compounds 1–10) with indications other than cancer are displayed in magenta ellipsoids, and their chemical structures are shown.
Figure 2
Figure 2. JAK/STAT signaling pathway. Various cytokines, such as interleukins, interferons, and neurotrophic factors, bind to their corresponding transmembrane receptors, leading to receptor dimerization. Then, JAKs are recruited to the intracellular region of receptors, resulting in the autophosphorylation of JAKs, which subsequently activates their respective STATs. STATs homodimerize/heterodimerize and then translocate into the nucleus to induce the transcription of various downstream targets associated with inflammation and cancer. IL, interleukin; IFN, interferon.
Figure 3
Figure 3. (A) Binding mode of tofacitinib to the ATP-binding site of JAK3 (PDB 3LXK). Tofacitinib forms two hydrogen bonds with Glu903 and Leu905. (B) Binding mode of BMS-986165 to TYK2 JH2 (PDB 6NZP). In addition to hydrophobic interactions, five hydrogen bonds between BMS-986165 and the Arg738, Lys642, Glu688, and Val690 residues can be observed.
Figure 4
Figure 4. Chemical structures of peficitinib, delgocitinib (approved in Japan), and other JAK inhibitors in clinical trials for nononcologic diseases (compounds 13–26).
Figure 5
Figure 5. Overview of BTK, SYK, PI3K/AKT/mTOR, MAPK, and related signaling pathways. SRC family kinases, such as Lyn in B/T cells or other cells, phosphorylate ITAM, which then recruits and activates SYK. SYK subsequently phosphorylates several substrates to activate various signaling pathways. SYK activates BTK-PLCγ, which then leads to activation of DAG-PKC and IP3-Ca2+, triggering MAPK signaling, AKT-mediated NF-κB signaling, and calcium mobilization. These pathways are associated with inflammation and cancer. PI3K/AKT/mTOR pathway: CD19, as a coreceptor of B- or T-cell receptors, is activated by Lyn, which then recruits and activates PI3K. PI3K generates PIP3, which recruits BTK and AKT. AKT activation by PDK1 and mTORC2 results in activation of mTORC2 and inhibition of GSK3. These downregulation targets are associated with inflammation, aging, neuropathy, and cancer. MAPK signaling includes the MKK4/7-JNK pathway, MKK3/4/6-p38 pathway, and MEK-ERK pathway. SYK activates the complex SLP65/GRB2/VAV/SOS, leading to activation of the MKK4/7-JNK pathway and MKK3/4/6-p38 pathway, which are associated with inflammation and cancer. PLC, phospholipase; DAG, diacyl glycerol; IP3, inositol triphosphate; IKK, IκB kinase; BCR/TCR, B/T-cell receptor; PIP2, phosphatidyl inositol 4,5-biphosphate; NFAT, nuclear factor of activated T-cells; ITAM, intracellular tyrosine activation; PDK1, 3-phosphoinositide dependent kinase-1; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; GRB2, growth factor receptor-bound protein 2.
Figure 6
Figure 6. (A) Irreversible binding mode of evobrutinib to BTK (PDB 6OMU). The covalent bond formed between Cys481 and evobrutinib is highlighted in purple. Evobrutinib forms three hydrogen bonds with the Thr474, Glu475, and Met477 residues. (B) Reversible binding mode of BMS-986142 to BTK (PDB 5T18). BMS-986142 forms two hydrogen bonds with Met477. For comparison, evobrutinib is depicted as a green stick model after superimposition of the X-ray crystal structure of 6OMU onto 5T18.
Figure 7
Figure 7. Chemical structures of BTK inhibitors approved (compounds 3, 27, and 28) or in clinical trials (compounds 29–37) for indications other than cancer.
Figure 8
Figure 8. Selected recently reported BTK inhibitors in preclinical studies.
Figure 9
Figure 9. ROCK signaling pathway. As a GTPase, Rho is activated by guanine nucleotide exchange factors (GEFs). Together with GTP, Rho then activates ROCK to phosphorylate various substrates. Among its substrates, ERM, NHE1, adducin, CRMP2, NF-L, MLC, and MARCKS are associated with cellular responses and cytoskeletal regulation. LIMK is involved in the regulation of F-actin stabilization. GEF, guanine nucleotide exchange factors; ERM, ezrin-radixin-moesin; NHE1, sodium hydrogen exchanger 1; CRMP2, myosin light chain phosphatase 2; NF-L, neurofilament protein; MLC, myosin light chain; MLCP, myosin light chain phosphatase; MARCKS, myristylated alanine-rich C-kinase; LIMK, LIM kinases 1 and 2.
Figure 10
Figure 10. (A) Chemical structures of ROCK inhibitors approved worldwide. (B) Binding mode of fasudil to ROCK2 (PDB 2F2U). In addition to hydrophobic interactions, three hydrogen bonds and an atypical hydrogen bond (CH···O═C) can be observed between fasudil and the Met172, Asn219, Asp232, and Glu170 residues.
Figure 11
Figure 11. Chemical structure of BA-1049 and compound 51 discussed in the text.
Figure 12
Figure 12. (A) Structure of tamatinib (52, R-406) and its prodrug fostamatinib (8). (B) Binding mode of tamatinib to SYK (PDB 3FQS). In addition to hydrophobic interactions, two hydrogen bonds, and an atypical hydrogen bond (CH···O═C) can be observed between tamatinib and Ala451 and Glu449.
Figure 13
Figure 13. Chemical structures of SYK inhibitors in clinical trials or in trials already being terminated.
Figure 14
Figure 14. (A) Chemical structure of sirolimus and its analogues approved for medical uses. (B) Binding mode of sirolimus to mTOR (PDB 4DRH). Sirolimus forms extensive hydrophobic interactions with surrounding residues, and four hydrogen bonds between this drug and the Asp68, Gly84, Ile87, and Tyr113 residues can be observed.
Figure 15
Figure 15. Reported mTOR inhibitors demonstrating efficacy in nononcologic disease models.
Figure 16
Figure 16. Chemical structures of PI3K inhibitors in clinical trials for nononcologic diseases.
Figure 17
Figure 17. (A) Binding mode of nemiralisib to PI3Kδ (PDB 5AE8). In addition to hydrophobic interactions, nemiralisib forms three hydrogen bonds with the Asp787, Glu826, and Val827 residues. (B) Key residues determining the selectivity of nemiralisib among PI3Kα, β, γ, and δ.
Figure 18
Figure 18. Chemical structures of recently reported PI3K inhibitors demonstrating interesting biological effects in nononcologic disease models.
Figure 19
Figure 19. (A) Chemical structure of omipalisib (GSK2126458). (B) Binding mode of omipalisib to PI3Kγ (PDB 3L08). Two hydrogen bonds are formed between omipalisib and the Ser806 and Val882 residues. In addition, a bridged hydrogen bond and one atypical CH···O═C hydrogen bond can be observed.
Figure 20
Figure 21
Figure 21. Chemical structures of a few FLT3 inhibitors discussed in the text.
Figure 22
Figure 22. Role of ASK1 in the MKK4/7-JNK and MKK3/4/6-p38 signaling pathways. ASK1 is activated by inflammatory cytokine signaling and oxidative stress, which then leads to activation of MKK4/7 and MKK3/4/6, triggering the JNK and p38 signaling pathways. RTKs, receptor tyrosine kinases; TRADD, tumor necrosis factor receptor-associated death protein; Daxx, death domain-associated protein; TRAF2, TNF receptor-associated factor 2.
Figure 23
Figure 23. Chemical structures of reported ASK1 inhibitors discussed in the text.
Figure 24
Figure 24. Binding mode of selonsertib to ASK1 (PDB 6OYT). Selonsertib forms two hydrogen bonds with Lys709 and Val757. In addition, it has extensive hydrophobic interactions with surrounding residues, including Leu686, Val694, Ala707, Met754, Val757, and Leu810.
Figure 25
Figure 25. Chemical structures of four reported selective RIPK1 inhibitors.
Figure 26
Figure 26. Binding mode of GSK2982772 to RIPK1 (PDB 5TX5). One hydrogen bond and a bridged hydrogen bond can be observed between GSK2982772 and the Asp156 and Val76 residues. GSK2982772 has extensive hydrophobic interactions with Val31, Ile43, Lys45, Met67, Leu70, Val75, Val76, Leu78, Leu90, Met92, Leu129, Val134, and Phe162.
Figure 27
Figure 27. Chemical structures of six reported selective RIPK2 inhibitors.
Figure 28
Figure 28. Binding mode of compound 100 to RIPK2 (PDB 6RNA). Three hydrogen bonds can be observed between 100 and Ser25, Met98, and Asp164. An atypical CH···O═C hydrogen bond can be found between 100 and Met98. Additionally, 100 has extensive hydrophobic interactions with Leu24, Ala45, Lys47, Leu70, Leu79, Ile93, Tyr97, Met98, Leu153, and Ala163.
Figure 29
Figure 29. Role of IRAK4 in the MKK3/4/6-p38 and MKK4/7-JNK signaling pathways. Once ligands such as LPS and IL-1 bind to the IL-1 receptor (IL-1R) and Toll-like receptors (TLRs), respectively, IRAK4 is recruited and activated by the adaptor protein MyD88. IRAK4 then activates IRAK1-TRAF6, stimulating the NF-κB, JNK and p38 pathways. In addition, IRAK1 activates IRAK2 to regulate the expression of caspase-8. FADD, Fas-associating protein with a novel death domain; Casp-8, caspase-8.
Figure 30
Figure 30. Chemical structures of IRAK4 inhibitors in clinical trials (A) and recently reported (B).
Figure 31
Figure 31. Binding mode of PF-06650833 to IRAK4 (PDB 5UIU). PF-06650833 forms three hydrogen bonds with Val263, Met265, and Ser328 and two bridged hydrogen bonds with Lys213 and Ser269.
Figure 32
Figure 32. GSK3 signaling pathway. GSK3 can be activated by PI3K signaling, regulating protein synthesis and glycogen synthesis. Binding of WNT to Frizzled and LRP5/6 complex results in recruitment and activation of Dsh protein, which then inhibits a protein complex containing GSK3, AXIN, APC, CKII, and β-catenin, blocking the phosphorylation and consequent degradation of β-catenin. Once D2 receptor activation occurs, β-arrestin brings AKT and GSK3 to PP2A. PP2A dephosphorylates AKT and GSK3, deactivating AKT and activating GSK3. LRP5/6, LDL receptor-related protein 5/6; PP2A, protein phosphatase 2A.
Figure 33
Figure 33. Chemical structures of GSK3 inhibitors in clinical trials.
Figure 34
Figure 34. Chemical structures of several recently reported GSK3 inhibitors.
Figure 35
Figure 35. Binding mode of BRD3937 to human GSK3β (PDB 5HLP). BRD3937 forms three hydrogen bonds with residues Asp133 and Val135.
Figure 36
Figure 36. (A) Chemical structures of BMS-751324 and MW150. (B) Binding mode of MW150 to human p38α MAPK (PDB 4R3C). MW150 forms hydrophobic interactions with surrounding residues; three hydrogen bonds between MW150 and the Lys53, Met109, and Ser154 residues can be observed.
Figure 37
Figure 37. (A) The deep and narrow ATP-binding site of MK2 (PDB 1NY3). An ADP (green ball and stick mode) is shown. (B) Binding mode of an analogue of compound 144 to MK2 (PDB 3FYJ). Two hydrogen bonds can be observed between this compound and Lys93 and Leu141. An atypical CH···O═C hydrogen bond can be found between this compound and Glu139. Additionally, this compound has extensive hydrophobic interactions with Leu70, Val78, Ala91, Lys93, Val118, Met138, Leu141, and Leu193.
Figure 38
Figure 38. Chemical structures of MK2 inhibitors discussed in the text.
Figure 39
Figure 39. TRK signaling pathway. Neurotrophins bind to TRK receptors, leading to recruitment of adaptor proteins, including GRB2, GAB1, SHC, SHP2, FRS2, and SOS. Subsequently, Ras, PLC-γ, and PI3K are activated, triggering the MAPK pathway, calcium mobilization, and the PI3K/AKT/mTOR pathway. These signaling pathways regulate gene expression activation, neurite outgrowth, and neuronal survival associated with pain and cancer.
Figure 40
Figure 40. Chemical structures of several reported TRK inhibitors.
Figure 41
Figure 41. (A) Binding mode of PF-06273340 (PDB 5JFX) to TRK-A. PF-06273340 forms three hydrogen bonds with the Met592 and Asp668 residues and two bridged hydrogen bonds with the Arg574 and Glu590 residues. (B) Binding mode of compound 152 (PDB 6D20) in an allosteric pocket of TRK-A. Compound 152 forms four hydrogen bonds with Leu486, Asp668, and Arg673. An NH+–π interaction can be observed. For comparison, PF-06273340 is shown as a green wire model.
Figure 42
Figure 42. Chemical structures of representative JNK inhibitors for treatment of nononcologic diseases.
Figure 43
Figure 43. Chemical structures of representative selective LRRK2 inhibitors.
Figure 44
Figure 44. Chemical structures of three reported KHK inhibitors.
Figure 45
Figure 45. Binding mode of PF-06835919 to KHK (PDB 6W0Z). Three hydrogen bonds with Arg108, Ala256, and Gly257 and a bridged hydrogen bond with Cys282 can be observed between PF-06835919 and KHK.
Figure 46
Figure 46. GRK2 signaling pathway. In the adrenal medulla and cardiac sympathetic nerve terminal, upregulation of GRK2 leads to α2 adrenergic receptor (α2AR) dysfunction, causing a massive release of catecholamines (norepinephrine and epinephrine). Catecholamines in turn stimulate the βARs present on cardiomyocytes, activating AKT and GRK2. GRK2 blocks sphingosine 1-phosphate (S1P) receptor 1 (S1PR1) signaling, which is involved in regulation of the contractile response and cardiac hypertrophy. In addition, GRK2 phosphorylates insulin receptor substrate-1 (IRS1), blocking glucose transporter type 4 (GLUT4) translocation from the cytosol to the plasma membrane. GRK2 also regulates β-oxidation rates and increases activation of the mitochondrial permeability transition pore (MPTP), which is associated with cellular death.
Figure 47
Figure 47. Chemical structures of representative GRK2 inhibitors discussed in the text.
Figure 48
Figure 48. Chemical structures of six NIK inhibitors discussed in the text.
Figure 49
Figure 49. Binding mode of compound 177 to murine NIK (PEB 6G4Z). Compound 177 forms hydrophobic interactions with surrounding residues, and four hydrogen bonds between this compound and residues Glu442, Glu472, Leu474, and Asp536 can be observed.
Figure 50
Figure 50. Chemical structures of a few reported selective PLK2 inhibitors.
Figure 51
Figure 51. Chemical structures of inhibitors of plasmodial kinases discussed in the text.
Figure 52
Figure 52. Chemical structures of TgCDPK1 inhibitors discussed in the text.
References
ARTICLE SECTIONSThis article references 359 other publications.
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- 14Punwani, N.; Scherle, P.; Flores, R.; Shi, J.; Liang, J.; Yeleswaram, S.; Levy, R.; Williams, W.; Gottlieb, A. Preliminary clinical activity of a topical JAK1/2 inhibitor in the treatment of psoriasis. J. Am. Acad. Dermatol. 2012, 67, 658– 664, DOI: 10.1016/j.jaad.2011.12.018[Crossref], [PubMed], [CAS], Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlOnsLrP&md5=9f1564cc0cc4726532aa0b4b5346d228Preliminary clinical activity of a topical JAK1/2 inhibitor in the treatment of psoriasisPunwani, Naresh; Scherle, Peggy; Flores, Robert; Shi, Jack; Liang, Jinjin; Yeleswaram, Swamy; Levy, Richard; Williams, William; Gottlieb, AliceJournal of the American Academy of Dermatology (2012), 67 (4), 658-664CODEN: JAADDB; ISSN:0190-9622. (Elsevier)Janus-assocd. kinases (JAKs) are involved in signal transduction from a variety of cytokines implicated in the pathogenesis of psoriasis, including interleukin (IL)-12, IL-23, and interferon-γ. INCB018424, a small mol. inhibitor of JAK1 and JAK2, inhibits cytokine-induced JAK/signal transducers and activators of transcription signaling and the resultant prodn. of inflammatory proteins (eg, IL-17). We sought to demonstrate proof of concept in patients with stable plaque psoriasis. Patients were dosed with vehicle, 0.5% or 1.0% INCB018424 phosphate cream once a day or 1.5% twice a day for 28 days. Addnl. groups included two active comparators (calcipotriene 0.005% cream or betamethasone dipropionate 0.05% cream). Both the 1% and the 1.5% cream improved lesion thickness, erythema, and scaling and reduced lesion area compared with placebo. A composite lesion score decreased by greater than 50% with the efficacious doses of INCB018424 compared with 32% for vehicle controls. Topical application of INCB018424 was well tolerated with few mild adverse events noted. Mean plasma concns. of INCB018424 after topical application of 0.5% to 1.5% cream were in the low nanomolar range, representing a fraction (<1%) of the half maximal inhibitory concn. (IC50) in whole blood for inhibition of cytokine-stimulated signal transducers and activators of transcription-3 phosphorylation. This study was limited by the relatively short study duration and small sample size. Topical INCB018424 is safe, is well tolerated, and exhibits clin. activity in the topical treatment of psoriasis.
- 15Bayart, C. B.; DeNiro, K. L.; Brichta, L.; Craiglow, B. G.; Sidbury, R. Topical Janus kinase inhibitors for the treatment of pediatric alopecia areata. J. Am. Acad. Dermatol. 2017, 77, 167– 170, DOI: 10.1016/j.jaad.2017.03.024[Crossref], [PubMed], [CAS], Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cnoslOitA%253D%253D&md5=8eb3104131bfeabeaed358e41d8a082bTopical Janus kinase inhibitors for the treatment of pediatric alopecia areataBayart Cheryl B; DeNiro Katherine L; Sidbury Robert; Brichta Lars; Craiglow Brittany GJournal of the American Academy of Dermatology (2017), 77 (1), 167-170 ISSN:.There is no expanded citation for this reference.
- 16Chrencik, J. E.; Patny, A.; Leung, I. K.; Korniski, B.; Emmons, T. L.; Hall, T.; Weinberg, R. A.; Gormley, J. A.; Williams, J. M.; Day, J. E.; Hirsch, J. L.; Kiefer, J. R.; Leone, J. W.; Fischer, H. D.; Sommers, C. D.; Huang, H. C.; Jacobsen, E. J.; Tenbrink, R. E.; Tomasselli, A. G.; Benson, T. E. Structural and thermodynamic characterization of the TYK2 and JAK3 kinase domains in complex with CP-690550 and CMP-6. J. Mol. Biol. 2010, 400, 413– 433, DOI: 10.1016/j.jmb.2010.05.020[Crossref], [PubMed], [CAS], Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXos1ylt7g%253D&md5=1b1efc3d6f913143dc9113e4ac1c4c60Structural and Thermodynamic Characterization of the TYK2 and JAK3 Kinase Domains in Complex with CP-690550 and CMP-6Chrencik, Jill E.; Patny, Akshay; Leung, Iris K.; Korniski, Brian; Emmons, Thomas L.; Hall, Troii; Weinberg, Robin A.; Gormley, Jennifer A.; Williams, Jennifer M.; Day, Jacqueline E.; Hirsch, Jeffrey L.; Kiefer, James R.; Leone, Joseph W.; Fischer, H. David; Sommers, Cynthia D.; Huang, Horng-Chih; Jacobsen, E. J.; Tenbrink, Ruth E.; Tomasselli, Alfredo G.; Benson, Timothy E.Journal of Molecular Biology (2010), 400 (3), 413-433CODEN: JMOBAK; ISSN:0022-2836. (Elsevier Ltd.)Janus kinases (JAKs) are crit. regulators of cytokine pathways and attractive targets of therapeutic value in both inflammatory and myeloproliferative diseases. Although the crystal structures of active JAK1 and JAK2 kinase domains have been reported recently with the clin. compd. CP-690550, the structures of both TYK2 and JAK3 with CP-690550 have remained outstanding. Here, we report the crystal structures of TYK2, a first in class structure, and JAK3 in complex with PAN-JAK inhibitors CP-690550 ((3R,4R)-3-[4-methyl-3-[N-methyl-N-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropionitrile) and CMP-6 (tetracyclic pyridone 2-t-butyl-9-fluoro-3,6-dihydro-7H-benz[h]-imidaz[4,5-f]isoquinoline-7-one), both of which bind in the ATP-binding cavities of both JAK isoenzymes in orientations similar to that obsd. in crystal structures of JAK1 and JAK2. Addnl., a complete thermodn. characterization of JAK/CP-690550 complex formation was completed by isothermal titrn. calorimetry, indicating the crit. role of the nitrile group from the CP-690550 compd. Finally, computational anal. using WaterMap further highlights the crit. positioning of the CP-690550 nitrile group in the displacement of an unfavorable water mol. beneath the glycine-rich loop. Taken together, the data emphasize the outstanding properties of the kinome-selective JAK inhibitor CP-690550, as well as the challenges in obtaining JAK isoenzyme-selective inhibitors due to the overall structural and sequence similarities between the TYK2, JAK1, JAK2 and JAK3 isoenzymes. Nevertheless, subtle amino acid variations of residues lining the ligand-binding cavity of the JAK enzymes, as well as the global positioning of the glycine-rich loop, might provide the initial clues to obtaining JAK-isoenzyme selective inhibitors.
- 17Moisan, A.; Lee, Y. K.; Zhang, J. D.; Hudak, C. S.; Meyer, C. A.; Prummer, M.; Zoffmann, S.; Truong, H. H.; Ebeling, M.; Kiialainen, A.; Gerard, R.; Xia, F.; Schinzel, R. T.; Amrein, K. E.; Cowan, C. A. White-to-brown metabolic conversion of human adipocytes by JAK inhibition. Nat. Cell Biol. 2015, 17, 57– 67, DOI: 10.1038/ncb3075[Crossref], [PubMed], [CAS], Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitV2nsrnK&md5=3b402af145e2806484068d374a93162fWhite-to-brown metabolic conversion of human adipocytes by JAK inhibitionMoisan, Annie; Lee, Youn-Kyoung; Zhang, Jitao David; Hudak, Carolyn S.; Meyer, Claas A.; Prummer, Michael; Zoffmann, Sannah; Truong, Hoa Hue; Ebeling, Martin; Kiialainen, Anna; Gerard, Regine; Xia, Fang; Schinzel, Robert T.; Amrein, Kurt E.; Cowan, Chad A.Nature Cell Biology (2015), 17 (1), 57-67CODEN: NCBIFN; ISSN:1465-7392. (Nature Publishing Group)The rising incidence of obesity and related disorders such as diabetes and heart disease has focused considerable attention on the discovery of new therapeutics. One promising approach has been to increase the no. or activity of brown-like adipocytes in white adipose depots, as this has been shown to prevent diet-induced obesity and reduce the incidence and severity of type 2 diabetes. Thus, the conversion of fat-storing cells into metabolically active thermogenic cells has become an appealing therapeutic strategy to combat obesity. Here, we report a screening platform for the identification of small mols. capable of promoting a white-to-brown metabolic conversion in human adipocytes. We identified two inhibitors of Janus kinase (JAK) activity with no precedent in adipose tissue biol. that stably confer brown-like metabolic activity to white adipocytes. Importantly, these metabolically converted adipocytes exhibit elevated UCP1 expression and increased mitochondrial activity. We further found that repression of interferon signalling and activation of hedgehog signalling in JAK-inactivated adipocytes contributes to the metabolic conversion obsd. in these cells. Our findings highlight a previously unknown role for the JAK-STAT pathway in the control of adipocyte function and establish a platform to identify compds. for the treatment of obesity.
- 18Al-Salama, Z. T.; Scott, L. J. Baricitinib: A Review in rheumatoid arthritis. Drugs 2018, 78, 761– 772, DOI: 10.1007/s40265-018-0908-4[Crossref], [PubMed], [CAS], Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXosFCrs7k%253D&md5=df956988c6927dd96c7fe5e547919dd3Baricitinib: A Review in Rheumatoid ArthritisAl-Salama, Zaina T.; Scott, Lesley J.Drugs (2018), 78 (7), 761-772CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)Baricitinib (Olumiant) is an oral, targeted synthetic DMARD that inhibits JAK1 and JAK2, which are implicated in the pathogenesis of rheumatoid arthritis (RA). This novel, small mol. is approved for use as monotherapy, or in combination with methotrexate, for the treatment of adults with moderate to severe active RA who responded inadequately to or were intolerant of ≥ 1 DMARD. In pivotal multinational trials, once-daily baricitinib 4 mg, with/without methotrexate (± another csDMARD), improved the signs and symptoms of RA, disease activity and phys. function in DMARD-naive patients and in patients with an inadequate response to methotrexate, csDMARDs or TNF inhibitors; baricitinib treatment also slowed structural joint damage in DMARD-naive patients and in those with an inadequate response to methotrexate and csDMARDs. Baricitinib plus methotrexate was more effective than adalimumab plus methotrexate in patients with an inadequate response to methotrexate. The onset of these benefits was generally rapid and sustained over time. Baricitinib was generally well tolerated during up to 5.5 years' treatment; the most commonly reported adverse drug reactions were upper respiratory tract infections, increased LDL cholesterol, nausea and thrombocytosis. Thus, once-daily baricitinib, as monotherapy or in combination with methotrexate, is an effective and generally well tolerated emerging treatment for patients with moderate to severe active RA who have responded inadequately to or are intolerant of ≥ 1 DMARD, and extends the options available for this population.
- 19Kunwar, S.; Collins, C. E.; Constantinescu, F. Baricitinib, a Janus kinase inhibitor, in the treatment of rheumatoid arthritis: a systematic literature review and meta-analysis of randomized controlled trials. Clin. Rheumatol. 2018, 37, 2611– 2620, DOI: 10.1007/s10067-018-4199-7[Crossref], [PubMed], [CAS], Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3c%252FotVOnuw%253D%253D&md5=663455a2aea96ec4b6c3f511e0dad888Baricitinib, a Janus kinase inhibitor, in the treatment of rheumatoid arthritis: a systematic literature review and meta-analysis of randomized controlled trialsKunwar Sumit; Collins Christopher E; Constantinescu FlorinaClinical rheumatology (2018), 37 (10), 2611-2620 ISSN:.Janus kinases (JAKs) play an important role in intracellular signaling for multiple cytokines in the pathogenesis of RA. Baricitinib is an oral, selective JAK 1 and 2 inhibitor which has been shown to be effective in the treatment of RA in several clinical trials. This meta-analysis aims to aggregate currently available data to assess the overall efficacy and safety of baricitinib in RA. We searched PubMed, EMBASE, and Cochrane CENTRAL from inception through 09/24/17 with restriction to English language. We excluded meeting abstracts without full text publication. We used RevMan 5.3 to perform meta-analysis between groups on baricitinib (2 and 4 mg daily) and placebo using random effect model calculating odds ratio (OR) as well as 95% confidence interval (CI). Compared to placebo, 2 mg of baricitinib was more effective in achieving ACR20 [54 vs. 36.6%; OR 2.09; 95% CI 1.60-2.71; p < 0.00001; I(2) 0%], ACR50 [31.6 vs. 10.3%; OR 2.3; 95% CI 1.68-3.15; p < 0.00001; I(2) 0%], and ACR70 responses [18.7 vs. 5.1%; OR 4.05; 95% CI 2.54-6.44; p < 0.00001; I(2) 0%]. Similarly, 4 mg of baricitinib daily was more effective than placebo. Baricitinib 2 mg once daily did not increase any adverse events [65.3 vs. 62.4%; OR 1.03; 95% CI 0.80-1.34; p = 0.8; I(2) 0%], serious adverse events [3.5 vs. 5%; OR 0.68; 95% CI 0.37-1.27; p = 0.22; I(2) 0%], and herpes zoster [1.2 vs. 0.4%; OR 2.34; 95% CI 0.27-20.47; p = 0.44; I(2) 37%] as compared to placebo. Similarly, 4 mg of baricitinib did not increase the risk of serious adverse events but increased herpes zoster infection [OR 3.88; 95% CI 1.36-11.06; p = 0.01; I(2) 0%] when compared to placebo. Baricitinib is effective in treatment of RA, and did not appear to have significant safety concerns during the first 6 months of treatment.
- 20Markham, A.; Keam, S. J. Peficitinib: first global approval. Drugs 2019, 79, 887– 891, DOI: 10.1007/s40265-019-01131-y[Crossref], [PubMed], [CAS], Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFWmtLzI&md5=eb2d2061829fc515854130050139871cPeficitinib: First Global ApprovalMarkham, Anthony; Keam, Susan J.Drugs (2019), 79 (8), 887-891CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)A review. Peficitinib [Smyraf (Astellas Pharma)] is a Janus kinase (JAK)1, JAK2, JAK3 and tyrosine kinase (Tyk)2 (pan-JAK) inhibitor recently approved in Japan for the treatment of rheumatoid arthritis. Inhibition of JAK suppresses the activation of cytokine signalling pathways involved in inflammation and joint destruction in rheumatoid arthritis. Peficitinib has been shown to significantly improve ACR20 and other measures of disease severity and to reduce the mean modified total Sharp score change from baseline in clin. trials. This article summarizes the milestones in the development of peficitinib leading to this first approval as a treatment for rheumatoid arthritis in patients who have an inadequate response to conventional therapies.
- 21Noji, S.; Hara, Y.; Miura, T.; Yamanaka, H.; Maeda, K.; Hori, A.; Yamamoto, H.; Obika, S.; Inoue, M.; Hase, Y.; Orita, T.; Doi, S.; Adachi, T.; Tanimoto, A.; Oki, C.; Kimoto, Y.; Ogawa, Y.; Negoro, T.; Hashimoto, H.; Shiozaki, M. Discovery of a janus kinase inhibitor bearing a highly three-dimensional spiro ccaffold: JTE-052 (Delgocitinib) as a new dermatological agent to treat inflammatory skin disorders. J. Med. Chem. 2020, 63, 7163– 7185, DOI: 10.1021/acs.jmedchem.0c00450[ACS Full Text], [CAS], Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtFWmsLrM&md5=f4eecf28446abb441f1436c41d8cb0a6Discovery of a Janus Kinase Inhibitor Bearing a Highly Three-Dimensional Spiro Scaffold: JTE-052 (Delgocitinib) as a New Dermatological Agent to Treat Inflammatory Skin DisordersNoji, Satoru; Hara, Yoshinori; Miura, Tomoya; Yamanaka, Hiroshi; Maeda, Katsuya; Hori, Akimi; Yamamoto, Hiroshi; Obika, Shingo; Inoue, Masafumi; Hase, Yasunori; Orita, Takuya; Doi, Satoki; Adachi, Tsuyoshi; Tanimoto, Atsuo; Oki, Chika; Kimoto, Yukari; Ogawa, Yoshihiro; Negoro, Tamotsu; Hashimoto, Hiromasa; Shiozaki, MakotoJournal of Medicinal Chemistry (2020), 63 (13), 7163-7185CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Dermatol. disorders such as atopic dermatitis arise from genetic and environmental causes and are complex and multifactorial in nature. Among possible risk factors, aberrant immunol. reactions are one of the leading etiologies. Immunosuppressive agents including topical steroids are common treatments for these disorders. Despite their reliability in clin. settings, topical steroids display side effects, typified by skin thinning. Accordingly, there is a need for alternate effective and well-tolerated therapies. As part of our efforts to investigate new immunomodulators, we have developed a series of JAK inhibitors, which incorporate novel three-dimensional spiro motifs and unexpectedly possess both excellent physicochem. properties and antidermatitis efficacy in the animal models. One of these compds., JTE-052 (ent-60), also known as delgocitinib, has been shown to be effective and well-tolerated in human clin. trials and has recently been approved in Japan for the treatment of atopic dermatitis as the first drug among Janus kinase inhibitors.
- 22Shan, S.; Zhou, Y.; Yu, J.; Yang, Q.; Pan, D.; Wang, Y.; Li, L.; Zhu, J.; Zhang, Y.; Huang, S.; Li, Z.; Ning, Z.; Xin, L.; Lu, X. Therapeutic treatment of a novel selective JAK3/JAK1/TBK1 inhibitor, CS12192, in rat and mouse models of rheumatoid arthritis. Int. Immunopharmacol. 2019, 77, 105914, DOI: 10.1016/j.intimp.2019.105914[Crossref], [PubMed], [CAS], Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitVaju7jE&md5=af003e55c8f149cd66b1632f19eb9f4dTherapeutic treatment of a novel selective JAK3/JAK1/TBK1 inhibitor, CS12192, in rat and mouse models of rheumatoid arthritisShan, Song; Zhou, You; Yu, Jindi; Yang, Qianjiao; Pan, Desi; Wang, Yanan; Li, Lingjie; Zhu, Jingzhong; Zhang, Yu; Huang, Shengjian; Li, Zhibin; Ning, Zhiqiang; Xin, Lijun; Lu, XianpingInternational Immunopharmacology (2019), 77 (), 105914CODEN: IINMBA; ISSN:1567-5769. (Elsevier B.V.)Rheumatoid arthritis (RA) is a representative autoimmune disease characterized by chronic inflammation and joint destruction. Although biol. inhibitors such as TNF-α and IL-6 antibodies have achieved success in clin. therapy, small mol. inhibitors against the Janus kinases (JAKs) involved in the signaling pathways of various cytokine receptors have gained more attraction as safe and efficacious options. In this study, we identified CS12192 as a novel selective JAK3/JAK1/TBK1 inhibitor and investigated its pharmacol. effects on the exptl. arthritis models in rat and mouse. We found that CS12192 showed a more selective inhibitory activity on JAK3, and to a less extent on JAK1 and TBK1, that were verified by decreased activation of p-STATs and p-IRF3 as well as down-regulation of IFN gene expression in the cultured cells with relevant stimuli. Furthermore, oral treatment with CS12192 dose-dependently ameliorated the disease severity, hind paw swelling, body wt. loss, and bone destruction in rat models of adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA). In a mouse CIA model, CS12192 also attenuated the disease severity, which was correlated with the suppressed CD4+ T cell activation and Th17 function, as well as the reduced cytokine levels in sera and pro-inflammatory cytokine and chemokine gene expression in joint tissue. Corroboratively, RANKL-induced osteoclast formation was inhibited by CS12192. Thus, these results suggest that CS12192 as a novel selective JAK inhibitor has therapeutic potential for the treatment of RA and may provide a new strategy for the control of autoimmune diseases.
- 23Fleischmann, R. Novel small-molecular therapeutics for rheumatoid arthritis. Curr. Opin. Rheumatol. 2012, 24, 335– 341, DOI: 10.1097/BOR.0b013e32835190ef[Crossref], [PubMed], [CAS], Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XkvFOmsLk%253D&md5=46627d79c7fe388c3a9d0fe05d83b040Novel small-molecular therapeutics for rheumatoid arthritisFleischmann, RoyCurrent Opinion in Rheumatology (2012), 24 (3), 335-341CODEN: CORHES; ISSN:1040-8711. (Lippincott Williams & Wilkins)Purpose of review: Since the introduction of biol. therapies into the treatment paradigm of rheumatoid arthritis (RA), there has been hope that oral small mol. immune modulators would be developed that would have a risk : benefit profile at least similar to biol. therapies, be more convenient for the patient and, hopefully, be less expensive. This article reviews the progress made in the development of these compds. over the past year. Recent findings: Addnl. information has become available in the past year on five oral compds. including kinase inhibitors (tofacitinib, fostamatinib, VX-509), an S1P lyase inhibitor (LX 3305) and a chemokine receptor-1 antagonist (CCX354-C). Efficacy has been shown in phase III with tofacitinib and in phase II with fostamatinib and VX-509; safety was the primary endpoint of the trials of CCX354-C and LX3305. Regarding side effects, liver test elevation and neutropenia occurred with tofacitinib, VX-509 and fostamatinib; lipid elevation with tofacitinib and VX-509; creatinine elevation and anemia with tofacitinib, and hypertension and diarrhea with fostamatinib. Summary: Compds. that inhibit tyrosine kinase pathways involved in cellular signalling have been shown to be effective in the treatment of RA with a reasonable risk : benefit ratio. It is too early to tell about inhibitors of other pathways.
- 24Bach, J.; Eastwood, P.; Gonzalez, J.; Gomez, E.; Alonso, J. A.; Fonquerna, S.; Lozoya, E.; Orellana, A.; Maldonado, M.; Calaf, E.; Alberti, J.; Perez, J.; Andres, A.; Prats, N.; Carreno, C.; Calama, E.; De Alba, J.; Calbet, M.; Miralpeix, M.; Ramis, I. Identification of 2-imidazopyridine and 2-aminopyridone purinones as potent pan-janus kinase (JAK) inhibitors for the inhaled treatment of respiratory diseases. J. Med. Chem. 2019, 62, 9045– 9060, DOI: 10.1021/acs.jmedchem.9b00533[ACS Full Text], [CAS], Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFCrs7%252FN&md5=39115f5f662922242340abd04394ffd8Identification of 2-Imidazopyridine and 2-Aminopyridone Purinones as Potent Pan-Janus Kinase (JAK) Inhibitors for the Inhaled Treatment of Respiratory DiseasesBach, Jordi; Eastwood, Paul; Gonzalez, Jacob; Gomez, Elena; Alonso, Juan Antonio; Fonquerna, Silvia; Lozoya, Estrella; Orellana, Adela; Maldonado, Monica; Calaf, Elena; Alberti, Joan; Perez, Juan; Andres, Ana; Prats, Neus; Carreno, Cristina; Calama, Elena; De Alba, Jorge; Calbet, Marta; Miralpeix, Montserrat; Ramis, IsabelJournal of Medicinal Chemistry (2019), 62 (20), 9045-9060CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Janus kinases (JAKs) have a key role in regulating the expression and function of relevant inflammatory cytokines involved in asthma and chronic obstructive pulmonary disease. Herein are described the design, synthesis, and pharmacol. evaluation of a series of novel purinone JAK inhibitors with profiles suitable for inhaled administration. Replacement of the imidazopyridine hinge binding motif present in the initial compds. of this series with a pyridone ring resulted in the mitigation of cell cytotoxicity. Further systematic structure-activity relationship (SAR) efforts driven by structural biol. studies led to the discovery of pyridone I, a potent pan-JAK inhibitor with good selectivity, long lung retention time, low oral bioavailability, and proven efficacy in the lipopolysaccharide-induced rat model of airway inflammation by the inhaled route.
- 25Farmer, L. J.; Ledeboer, M. W.; Hoock, T.; Arnost, M. J.; Bethiel, R. S.; Bennani, Y. L.; Black, J. J.; Brummel, C. L.; Chakilam, A.; Dorsch, W. A.; Fan, B.; Cochran, J. E.; Halas, S.; Harrington, E. M.; Hogan, J. K.; Howe, D.; Huang, H.; Jacobs, D. H.; Laitinen, L. M.; Liao, S.; Mahajan, S.; Marone, V.; Martinez-Botella, G.; McCarthy, P.; Messersmith, D.; Namchuk, M.; Oh, L.; Penney, M. S.; Pierce, A. C.; Raybuck, S. A.; Rugg, A.; Salituro, F. G.; Saxena, K.; Shannon, D.; Shlyakter, D.; Swenson, L.; Tian, S. K.; Town, C.; Wang, J.; Wang, T.; Wannamaker, M. W.; Winquist, R. J.; Zuccola, H. J. Discovery of VX-509 (Decernotinib): a potent and selective janus kinase 3 inhibitor for the treatment of autoimmune diseases. J. Med. Chem. 2015, 58, 7195– 7216, DOI: 10.1021/acs.jmedchem.5b00301[ACS Full Text], [CAS], Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1KmsbbO&md5=8ba1e0beb7570baaf68fd5f20b54f9f9Discovery of VX-509 (Decernotinib): A Potent and Selective Janus Kinase 3 Inhibitor for the Treatment of Autoimmune DiseasesFarmer, Luc J.; Ledeboer, Mark W.; Hoock, Thomas; Arnost, Michael J.; Bethiel, Randy S.; Bennani, Youssef L.; Black, James J.; Brummel, Christopher L.; Chakilam, Ananthsrinivas; Dorsch, Warren A.; Fan, Bin; Cochran, John E.; Halas, Summer; Harrington, Edmund M.; Hogan, James K.; Howe, David; Huang, Hui; Jacobs, Dylan H.; Laitinen, Leena M.; Liao, Shengkai; Mahajan, Sudipta; Marone, Valerie; Martinez-Botella, Gabriel; McCarthy, Pamela; Messersmith, David; Namchuk, Mark; Oh, Luke; Penney, Marina S.; Pierce, Albert C.; Raybuck, Scott A.; Rugg, Arthur; Salituro, Francesco G.; Saxena, Kumkum; Shannon, Dean; Shlyakter, Dina; Swenson, Lora; Tian, Shi-Kai; Town, Christopher; Wang, Jian; Wang, Tiansheng; Wannamaker, M. Woods; Winquist, Raymond J.; Zuccola, Harmon J.Journal of Medicinal Chemistry (2015), 58 (18), 7195-7216CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)While several therapeutic options exist, the need for more effective, safe, and convenient treatment for a variety of autoimmune diseases persists. Targeting the Janus tyrosine kinases (JAKs), which play essential roles in cell signaling responses and can contribute to aberrant immune function assocd. with disease, has emerged as a novel and attractive approach for the development of new autoimmune disease therapies. We screened our compd. library against JAK3, a key signaling kinase in immune cells, and identified multiple scaffolds showing good inhibitory activity for this kinase. A particular scaffold of interest, the 1H-pyrrolo[2,3-b]pyridine series (7-azaindoles), was selected for further optimization in part on the basis of binding affinity (Ki) as well as on the basis of cellular potency. Optimization of this chem. series led to the identification of VX-509 (decernotinib), a novel, potent, and selective JAK3 inhibitor, which demonstrates good efficacy in vivo in the rat host vs. graft model (HvG). On the basis of these findings, it appears that VX-509 offers potential for the treatment of a variety of autoimmune diseases.
- 26Chang, Y.; Xu, S.; Ding, K. Tyrosine kinase 2 (TYK2) allosteric inhibitors to treat autoimmune diseases. J. Med. Chem. 2019, 62, 8951– 8952, DOI: 10.1021/acs.jmedchem.9b01612[ACS Full Text], [CAS], Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFeqtrjK&md5=d8214c7fca197889246df48f29e5c5e5Tyrosine Kinase 2 (TYK2) Allosteric Inhibitors To Treat Autoimmune DiseasesChang, Yu; Xu, Shilin; Ding, KeJournal of Medicinal Chemistry (2019), 62 (20), 8951-8952CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. TYK2 is an emerging drug target for various human autoimmune diseases. However, discovery of selective TYK2 inhibitor over other JAK family members (i.e., JAK1, 2, 3) by targeting the catalytically active site (Janus Homolog 1 (JH1) domain) is challenging. This Viewpoint discusses the discovery of a series of N-Me pyridazine-3-carboxamides as novel selective pseudokinase (JH2) domain binders of TYK2. A systematic structure-based optimization yielded a highly potent and selective allosteric TYK2 inhibitor candidate that is currently in phase III clin. trial for psoriasis.
- 27Moslin, R.; Zhang, Y.; Wrobleski, S. T.; Lin, S.; Mertzman, M.; Spergel, S.; Tokarski, J. S.; Strnad, J.; Gillooly, K.; McIntyre, K. W.; Zupa-Fernandez, A.; Cheng, L.; Sun, H.; Chaudhry, C.; Huang, C.; D’Arienzo, C.; Heimrich, E.; Yang, X.; Muckelbauer, J. K.; Chang, C.; Tredup, J.; Mulligan, D.; Xie, D.; Aranibar, N.; Chiney, M.; Burke, J. R.; Lombardo, L.; Carter, P. H.; Weinstein, D. S. Identification of N-methyl nicotinamide and N-methyl pyridazine-3-carboxamide pseudokinase domain ligands as highly selective allosteric inhibitors of tyrosine kinase 2 (TYK2). J. Med. Chem. 2019, 62, 8953– 8972, DOI: 10.1021/acs.jmedchem.9b00443[ACS Full Text], [CAS], Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtlOltbrO&md5=869bfe303f0743867b8c9eb8201707c3Identification of N-Methyl Nicotinamide and N-Methyl Pyridazine-3-Carboxamide Pseudokinase Domain Ligands as Highly Selective Allosteric Inhibitors of Tyrosine Kinase 2 (TYK2)Moslin, Ryan; Zhang, Yanlei; Wrobleski, Stephen T.; Lin, Shuqun; Mertzman, Michael; Spergel, Steven; Tokarski, John S.; Strnad, Joann; Gillooly, Kathleen; McIntyre, Kim W.; Zupa-Fernandez, Adriana; Cheng, Lihong; Sun, Huadong; Chaudhry, Charu; Huang, Christine; D'Arienzo, Celia; Heimrich, Elizabeth; Yang, Xiaoxia; Muckelbauer, Jodi K.; Chang, ChiehYing; Tredup, Jeffrey; Mulligan, Dawn; Xie, Dianlin; Aranibar, Nelly; Chiney, Manoj; Burke, James R.; Lombardo, Louis; Carter, Percy H.; Weinstein, David S.Journal of Medicinal Chemistry (2019), 62 (20), 8953-8972CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)As a member of the Janus (JAK) family of nonreceptor tyrosine kinases, TYK2 plays an important role in mediating the signaling of pro-inflammatory cytokines including IL-12, IL-23, and type 1 interferons. The nicotinamide 4, identified by a SPA-based high-throughput screen targeting the TYK2 pseudokinase domain, potently inhibits IL-23 and IFNα signaling in cellular assays. The described work details the optimization of this poorly selective hit (4) to potent and selective mols. such as 47 and 48. The discoveries described herein were crit. to the eventual identification of the clin. TYK2 JH2 inhibitor (see following report in this issue). Compd. 48 provided robust inhibition in a mouse IL-12-induced IFNγ pharmacodynamic model as well as efficacy in an IL-23 and IL-12-dependent mouse colitis model. These results demonstrate the ability of TYK2 JH2 domain binders to provide a highly selective alternative to conventional TYK2 orthosteric inhibitors.
- 28Wrobleski, S. T.; Moslin, R.; Lin, S.; Zhang, Y.; Spergel, S.; Kempson, J.; Tokarski, J. S.; Strnad, J.; Zupa-Fernandez, A.; Cheng, L.; Shuster, D.; Gillooly, K.; Yang, X.; Heimrich, E.; McIntyre, K. W.; Chaudhry, C.; Khan, J.; Ruzanov, M.; Tredup, J.; Mulligan, D.; Xie, D.; Sun, H.; Huang, C.; D’Arienzo, C.; Aranibar, N.; Chiney, M.; Chimalakonda, A.; Pitts, W. J.; Lombardo, L.; Carter, P. H.; Burke, J. R.; Weinstein, D. S. Highly selective inhibition of tyrosine kinase 2 (TYK2) for the treatment of autoimmune diseases: discovery of the allosteric inhibitor BMS-986165. J. Med. Chem. 2019, 62, 8973– 8995, DOI: 10.1021/acs.jmedchem.9b00444[ACS Full Text], [CAS], Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtlyht7%252FP&md5=ca161c470df002b0bdd2bf6b19920adaHighly Selective Inhibition of Tyrosine Kinase 2 (TYK2) for the Treatment of Autoimmune Diseases: Discovery of the Allosteric Inhibitor BMS-986165Wrobleski, Stephen T.; Moslin, Ryan; Lin, Shuqun; Zhang, Yanlei; Spergel, Steven; Kempson, James; Tokarski, John S.; Strnad, Joann; Zupa-Fernandez, Adriana; Cheng, Lihong; Shuster, David; Gillooly, Kathleen; Yang, Xiaoxia; Heimrich, Elizabeth; McIntyre, Kim W.; Chaudhry, Charu; Khan, Javed; Ruzanov, Max; Tredup, Jeffrey; Mulligan, Dawn; Xie, Dianlin; Sun, Huadong; Huang, Christine; D'Arienzo, Celia; Aranibar, Nelly; Chiney, Manoj; Chimalakonda, Anjaneya; Pitts, William J.; Lombardo, Louis; Carter, Percy H.; Burke, James R.; Weinstein, David S.Journal of Medicinal Chemistry (2019), 62 (20), 8973-8995CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Small mol. JAK inhibitors have emerged as a major therapeutic advancement in treating autoimmune diseases. The discovery of isoform selective JAK inhibitors that traditionally target the catalytically active site of this kinase family has been a formidable challenge. Our strategy to achieve high selectivity for TYK2 relies on targeting the TYK2 pseudokinase (JH2) domain. Herein we report the late stage optimization efforts including a structure-guided design and water displacement strategy that led to the discovery of BMS-986165 (11, I) as a high affinity JH2 ligand and potent allosteric inhibitor of TYK2. In addn. to unprecedented JAK isoform and kinome selectivity, I shows excellent pharmacokinetic properties with minimal profiling liabilities and is efficacious in several murine models of autoimmune disease. On the basis of these findings, I appears differentiated from all other reported JAK inhibitors and has been advanced as the first pseudokinase-directed therapeutic in clin. development as an oral treatment for autoimmune diseases.
- 29Feng, Y.; Duan, W.; Cu, X.; Liang, C.; Xin, M. Bruton’s tyrosine kinase (BTK) inhibitors in treating cancer: a patent review (2010–2018). Expert Opin. Ther. Pat. 2019, 29, 217– 241, DOI: 10.1080/13543776.2019.1594777[Crossref], [PubMed], [CAS], Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXnt1Wrsbo%253D&md5=2f31c214c46945f7818532a39430ec00Bruton's tyrosine kinase (BTK) inhibitors in treating cancer: a patent review (2010-2018)Feng, Yifan; Duan, Weiming; Cu, Xiaochuan; Liang, Chengyuan; Xin, MinhangExpert Opinion on Therapeutic Patents (2019), 29 (4), 217-241CODEN: EOTPEG; ISSN:1354-3776. (Taylor & Francis Ltd.)A review. Bruton's tyrosine kinase (BTK) plays a crit. role in the regulation of survival, proliferation, activation and differentiation of B-lineage cells. It participates by regulating multiple cellular signaling pathways, including B cell receptor and FcR signaling cascades. BTK is abundantly expressed and constitutively active in the pathogenesis of B cell hematol. malignancies, as well as several autoimmune diseases. Therefore, BTK is considered as an attractive target for treatment of B-lineage lymphomas, leukemias, and some autoimmune diseases. Many industry and academia efforts have been made to explore small mol. BTK inhibitors. This review aims to provide an overview of the patented BTK inhibitors for the treatment of cancer from 2010 to 2018. BTK inhibitors attract much interest for their therapeutic potential in the treatment of cancers and autoimmune diseases, esp. for B cell hematol. malignancies. In 2013, ibrutinib was approved by the FDA as the first-in-class BTK inhibitors for the treatment of mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), and now it is also undergoing clin. evaluation for other indications in either single or combined therapy. It is clear that BTK inhibitors can provide a promising clin. benefit in treating B-lineage lymphomas and leukemias.
- 30Rip, J.; Van Der Ploeg, E. K.; Hendriks, R. W.; Corneth, O. B. J. The role of Bruton’s tyrosine kinase in immune cell signaling and systemic autoimmunity. Crit. Rev. Immunol. 2018, 38, 17– 62, DOI: 10.1615/CritRevImmunol.2018025184[Crossref], [PubMed], [CAS], Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MjovFWksw%253D%253D&md5=0aad71e4f9349f97b7d81eb2739931dfThe Role of Bruton's Tyrosine Kinase in Immune Cell Signaling and Systemic AutoimmunityRip Jasper; Van Der Ploeg Esmee K; Hendriks Rudi W; Corneth Odilia B JCritical reviews in immunology (2018), 38 (1), 17-62 ISSN:1040-8401.Bruton's tyrosine kinase (BTK) is an intracellular signaling molecule first identified as the molecule affected in X-linked agammaglobulinemia (XLA) patients, who almost completely lack peripheral B cells and serum immunoglobulins. BTK is crucial for B cell development and various B cell functions, including cytokine and natural antibody production. Importantly, it is also expressed in numerous other cells, including monocytes, macrophages, granulocytes, dendritic cells, and osteoclasts. A few rare cases of autoimmune disease in XLA patients have been described. Interestingly, increased BTK protein expression in patients with systemic autoimmune disease appears to be correlated with autoantibody production. In addition, BTK may promote autoimmunity as an important driver of an imbalance in B-T cell interaction. Because of this overwhelming evidence of a pathogenic role of BTK in autoimmunity, several clinical trials in rheumatoid arthritis and systemic lupus erythematosus patients with BTK inhibitors are currently running. Here, we review BTK function in different signaling pathways and in different cell lineages, focusing on the growing body of literature indicating a critical role for BTK in autoimmunity. We also discuss BTK and the promising results of BTK inhibition in animal models of autoimmune disease.
- 31Di Paolo, J. A.; Huang, T.; Balazs, M.; Barbosa, J.; Barck, K. H.; Bravo, B. J.; Carano, R. A.; Darrow, J.; Davies, D. R.; DeForge, L. E.; Diehl, L.; Ferrando, R.; Gallion, S. L.; Giannetti, A. M.; Gribling, P.; Hurez, V.; Hymowitz, S. G.; Jones, R.; Kropf, J. E.; Lee, W. P.; Maciejewski, P. M.; Mitchell, S. A.; Rong, H.; Staker, B. L.; Whitney, J. A.; Yeh, S.; Young, W. B.; Yu, C.; Zhang, J.; Reif, K.; Currie, K. S. Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis. Nat. Chem. Biol. 2011, 7, 41– 50, DOI: 10.1038/nchembio.481[Crossref], [PubMed], [CAS], Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVOrsLjP&md5=99d925c71bc1b201191ebde0f1c0b50fSpecific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritisDi Paolo, Julie A.; Huang, Tao; Balazs, Mercedesz; Barbosa, James; Barck, Kai H.; Bravo, Brandon J.; Carano, Richard A. D.; Darrow, James; Davies, Douglas R.; DeForge, Laura E.; Diehl, Lauri; Ferrando, Ronald; Gallion, Steven L.; Giannetti, Anthony M.; Gribling, Peter; Hurez, Vincent; Hymowitz, Sarah G.; Jones, Randall; Kropf, Jeffrey E.; Lee, Wyne P.; Maciejewski, Patricia M.; Mitchell, Scott A.; Rong, Hong; Staker, Bart L.; Whitney, J. Andrew; Yeh, Sherry; Young, Wendy B.; Yu, Christine; Zhang, Juan; Reif, Karin; Currie, Kevin S.Nature Chemical Biology (2011), 7 (1), 41-50CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)Bruton's tyrosine kinase (Btk) is a therapeutic target for rheumatoid arthritis, but the cellular and mol. mechanisms by which Btk mediates inflammation are poorly understood. Here we describe the discovery of CGI1746, a small-mol. Btk inhibitor chemotype with a new binding mode that stabilizes an inactive nonphosphorylated enzyme conformation. CGI1746 has exquisite selectivity for Btk and inhibits both auto- and transphosphorylation steps necessary for enzyme activation. Using CGI1746, we demonstrate that Btk regulates inflammatory arthritis by two distinct mechanisms. CGI1746 blocks B cell receptor-dependent B cell proliferation and in prophylactic regimens reduces autoantibody levels in collagen-induced arthritis. In macrophages, Btk inhibition abolishes FcγRIII-induced TNFα, IL-1β and IL-6 prodn. Accordingly, in myeloid- and FcγR-dependent autoantibody-induced arthritis, CGI1746 decreases cytokine levels within joints and ameliorates disease. These results provide new understanding of the function of Btk in both B cell- or myeloid cell-driven disease processes and provide a compelling rationale for targeting Btk in rheumatoid arthritis.
- 32Liang, C.; Tian, D.; Ren, X.; Ding, S.; Jia, M.; Xin, M.; Thareja, S. The development of Bruton’s tyrosine kinase (BTK) inhibitors from 2012 to 2017: A mini-review. Eur. J. Med. Chem. 2018, 151, 315– 326, DOI: 10.1016/j.ejmech.2018.03.062[Crossref], [PubMed], [CAS], Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXnt1ehtL0%253D&md5=1ea0bf36d8ebadbfba624f858911b182The development of Bruton's tyrosine kinase (BTK) inhibitors from 2012 to 2017: A mini-reviewLiang, Chengyuan; Tian, Danni; Ren, Xiaodong; Ding, Shunjun; Jia, Minyi; Xin, Minhang; Thareja, SureshEuropean Journal of Medicinal Chemistry (2018), 151 (), 315-326CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)A review. Bruton's tyrosine kinase (BTK) has emerged as a promising drug target for multiple diseases, particularly hematopoietic malignancies and autoimmune diseases related to B lymphocytes. This review focuses on the diverse, small-mol. inhibitors of BTK kinase that have shown good prospects for clin. application. Individual examples of these inhibitors, including both reversible and irreversible inhibitors and a recently developed reversible covalent inhibitor of BTK, are discussed. Considerable progress has been made in the development of irreversible inhibitors, most of which target the SH3 pocket and the cysteine 481 residue of BTK. The present review also surveys the pharmacol. advantages and deficiencies of both reversible and irreversible BTK drugs, with a focus on the structure-activity relationship (SARs) and binding modes of representative drugs, which could inspire crit. thinking and new ideas for developing potent BTK inhibitors with less unwanted off-target effects.
- 33Akinleye, A.; Chen, Y.; Mukhi, N.; Song, Y.; Liu, D. Ibrutinib and novel BTK inhibitors in clinical development. J. Hematol. Oncol. 2013, 6, 59, DOI: 10.1186/1756-8722-6-59[Crossref], [PubMed], [CAS], Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVagtrjI&md5=e5067b998c61818e2efbb62da935b490Ibrutinib and novel BTK inhibitors in clinical developmentAkinleye, Akintunde; Chen, Yamei; Mukhi, Nikhil; Song, Yongping; Liu, DelongJournal of Hematology & Oncology (2013), 6 (), 59CODEN: JHOOAO; ISSN:1756-8722. (BioMed Central Ltd.)A review. Small mol. inhibitors targeting dysregulated pathways (RAS/RAF/MEK, PI3K/AKT/mTOR, JAK/STAT) have significantly improved clin. outcomes in cancer patients. Recently Bruton's tyrosine kinase (BTK), a crucial terminal kinase enzyme in the B-cell antigen receptor (BCR) signaling pathway, has emerged as an attractive target for therapeutic intervention in human malignancies and autoimmune disorders. Ibrutinib, a novel first-in-human BTK inhibitor, has demonstrated clin. effectiveness and tolerability in early clin. trials and has progressed into phase III trials. However, addnl. research is necessary to identify the optimal dosing schedule, as well as patients most likely to benefit from BTK inhibition. This review summarizes preclin. and clin. development of ibrutinib and other novel BTK inhibitors (GDC-0834, CGI-560, CGI-1746, HM-71224, CC-292 and ONO-4059, CNX-774, LFM-A13) in the treatment of B-cell malignancies and autoimmune disorders.
- 34de Weerdt, I.; Koopmans, S. M.; Kater, A. P.; van Gelder, M. Incidence and management of toxicity associated with ibrutinib and idelalisib: a practical approach. Haematologica 2017, 102, 1629– 1639, DOI: 10.3324/haematol.2017.164103[Crossref], [PubMed], [CAS], Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitV2js7jE&md5=63198531f21c5cc5ca64ead536e5684aIncidence and management of toxicity associated with ibrutinib and idelalisib: a practical approachde Weerdt, Iris; Koopmans, Suzanne M.; Kater, Arnon P.; Van Gelder, MichelHaematologica (2017), 102 (10), 1629-1639CODEN: HAEMAX; ISSN:1592-8721. (Ferrata Storti Foundation)The use of novel B-cell receptor signaling inhibitors results in high response rates and long progression-free survival in patients with indolent B-cell malignancies, such as chronic lymphocytic leukemia, follicular lymphoma, mantle cell lymphoma and Waldenstrom macroglobulinemia. Ibrutinib, the first-in-class inhibitor of Bruton tyrosine kinase, and idelalisib, the first-in-class inhibitor of phosphatidylinositol 3-kinase α, have recently been approved for the treatment of several indolent B-cell malignancies. These drugs are esp. being used for previously unmet needs, i.e., for patients with relapsed or refractory disease, high-risk cytogenetic or mol. abnormalities, or with comorbidities. Treatment with ibrutinib and idelalisib is generally well tolerated, even by elderly patients. However, the use of these drugs may come with toxicities that are distinct from the side effects of immunochemotherapy. In this review we discuss the most commonly reported and/or most clin. relevant adverse events assocd. with these B-cell receptor inhibitors, with special emphasis on recommendations for their management.
- 35Wu, J.; Zhang, M.; Liu, D. Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. J. Hematol. Oncol. 2016, 9, 21, DOI: 10.1186/s13045-016-0250-9[Crossref], [PubMed], [CAS], Google Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXis1eisrw%253D&md5=a6a8f9b9236abe7ef1054a41e1c71e5aAcalabrutinib (ACP-196): a selective second-generation BTK inhibitorWu, Jingjing; Zhang, Mingzhi; Liu, DelongJournal of Hematology & Oncology (2016), 9 (), 21/1-21/4CODEN: JHOOAO; ISSN:1756-8722. (BioMed Central Ltd.)More and more targeted agents become available for B cell malignancies with increasing precision and potency. The first-in-class Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, has been in clin. use for the treatment of chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's macroglobulinemia. More selective BTK inhibitors (ACP-196, ONO/GS-4059, BGB-3111, CC-292) are being explored. Acalabrutinib (ACP-196) is a novel irreversible second-generation BTK inhibitor that was shown to be more potent and selective than ibrutinib. This review summarized the preclin. research and clin. data of acalabrutinib.
- 36Guo, Y.; Liu, Y.; Hu, N.; Yu, D.; Zhou, C.; Shi, G.; Zhang, B.; Wei, M.; Liu, J.; Luo, L.; Tang, Z.; Song, H.; Guo, Y.; Liu, X.; Su, D.; Zhang, S.; Song, X.; Zhou, X.; Hong, Y.; Chen, S.; Cheng, Z.; Young, S.; Wei, Q.; Wang, H.; Wang, Q.; Lv, L.; Wang, F.; Xu, H.; Sun, H.; Xing, H.; Li, N.; Zhang, W.; Wang, Z.; Liu, G.; Sun, Z.; Zhou, D.; Li, W.; Liu, L.; Wang, L.; Wang, Z. Discovery of Zanubrutinib (BGB-3111), a novel, potent, and selective covalent inhibitor of Bruton’s tyrosine kinase. J. Med. Chem. 2019, 62, 7923– 7940, DOI: 10.1021/acs.jmedchem.9b00687[ACS Full Text], [CAS], Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsFSku7bP&md5=5cdb551d296e60eb1e82b03b7a0384eeDiscovery of Zanubrutinib (BGB-3111), a Novel, Potent, and Selective Covalent Inhibitor of Bruton's Tyrosine KinaseGuo, Yunhang; Liu, Ye; Hu, Nan; Yu, Desheng; Zhou, Changyou; Shi, Gongyin; Zhang, Bo; Wei, Min; Liu, Junhua; Luo, Lusong; Tang, Zhiyu; Song, Huipeng; Guo, Yin; Liu, Xuesong; Su, Dan; Zhang, Shuo; Song, Xiaomin; Zhou, Xing; Hong, Yuan; Chen, Shuaishuai; Cheng, Zhenzhen; Young, Steve; Wei, Qiang; Wang, Haisheng; Wang, Qiuwen; Lv, Lei; Wang, Fan; Xu, Haipeng; Sun, Hanzi; Xing, Haimei; Li, Na; Zhang, Wei; Wang, Zhongbo; Liu, Guodong; Sun, Zhijian; Zhou, Dongping; Li, Wei; Liu, Libin; Wang, Lai; Wang, ZhiweiJournal of Medicinal Chemistry (2019), 62 (17), 7923-7940CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Aberrant activation of Bruton's tyrosine kinase (BTK) plays an important role in pathogenesis of B-cell lymphomas, suggesting that inhibition of BTK is useful in the treatment of hematol. malignancies. The discovery of a more selective on-target covalent BTK inhibitor is of high value. Herein, we disclose the discovery and preclin. characterization of a potent, selective, and irreversible BTK inhibitor as our clin. candidate by using in vitro potency, selectivity, pharmacokinetics (PK), and in vivo pharmacodynamic for prioritizing compds. Compd. BGB-3111 (31a, Zanubrutinib) demonstrates (i) potent activity against BTK and excellent selectivity over other TEC, EGFR and Src family kinases, (ii) desirable ADME, excellent in vivo pharmacodynamic in mice and efficacy in OCI-LY10 xenograft models.
- 37Caldwell, R. D.; Qiu, H.; Askew, B. C.; Bender, A. T.; Brugger, N.; Camps, M.; Dhanabal, M.; Dutt, V.; Eichhorn, T.; Gardberg, A. S.; Goutopoulos, A.; Grenningloh, R.; Head, J.; Healey, B.; Hodous, B. L.; Huck, B. R.; Johnson, T. L.; Jones, C.; Jones, R. C.; Mochalkin, I.; Morandi, F.; Nguyen, N.; Meyring, M.; Potnick, J. R.; Santos, D. C.; Schmidt, R.; Sherer, B.; Shutes, A.; Urbahns, K.; Follis, A. V.; Wegener, A. A.; Zimmerli, S. C.; Liu-Bujalski, L. Discovery of evobrutinib: an oral, potent, and highly selective, covalent Bruton’s tyrosine kinase (BTK) inhibitor for the treatment of immunological diseases. J. Med. Chem. 2019, 62, 7643– 7655, DOI: 10.1021/acs.jmedchem.9b00794[ACS Full Text], [CAS], Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsV2jtr7P&md5=f9711d8a18803afc356dbac848067acfDiscovery of Evobrutinib: An Oral, Potent, and Highly Selective, Covalent Bruton's Tyrosine Kinase (BTK) Inhibitor for the Treatment of Immunological DiseasesCaldwell, Richard D.; Qiu, Hui; Askew, Ben C.; Bender, Andrew T.; Brugger, Nadia; Camps, Montserrat; Dhanabal, Mohanraj; Dutt, Vikram; Eichhorn, Thomas; Gardberg, Anna S.; Goutopoulos, Andreas; Grenningloh, Roland; Head, Jared; Healey, Brian; Hodous, Brian L.; Huck, Bayard R.; Johnson, Theresa L.; Jones, Christopher; Jones, Reinaldo C.; Mochalkin, Igor; Morandi, Federica; Nguyen, Ngan; Meyring, Michael; Potnick, Justin R.; Santos, Dusica Cvetinovic; Schmidt, Ralf; Sherer, Brian; Shutes, Adam; Urbahns, Klaus; Follis, Ariele Viacava; Wegener, Ansgar A.; Zimmerli, Simone C.; Liu-Bujalski, LesleyJournal of Medicinal Chemistry (2019), 62 (17), 7643-7655CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Bruton's tyrosine kinase (BTK) inhibitors such as ibrutinib hold a prominent role in the treatment of B cell malignancies. However, further refinement is needed to this class of agents, particularly in terms of adverse events (potentially driven by kinase promiscuity), which preclude their evaluation in nononcol. indications. Here, we report the discovery and preclin. characterization of evobrutinib, a potent, obligate covalent inhibitor with high kinase selectivity. Evobrutinib displayed sufficient preclin. pharmacokinetic and pharmacodynamic characteristics which allowed for in vivo evaluation in efficacy models. Moreover, the high selectivity of evobrutinib for BTK over epidermal growth factor receptor and other Tec family kinases suggested a low potential for off-target related adverse effects. Clin. investigation of evobrutinib is ongoing in several autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus.
- 38Evans, E. K.; Tester, R.; Aslanian, S.; Karp, R.; Sheets, M.; Labenski, M. T.; Witowski, S. R.; Lounsbury, H.; Chaturvedi, P.; Mazdiyasni, H.; Zhu, Z.; Nacht, M.; Freed, M. I.; Petter, R. C.; Dubrovskiy, A.; Singh, J.; Westlin, W. F. Inhibition of btk with cc-292 provides early pharmacodynamic assessment of activity in mice and humans. J. Pharmacol. Exp. Ther. 2013, 346, 219– 228, DOI: 10.1124/jpet.113.203489[Crossref], [PubMed], [CAS], Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFOjsbbM&md5=95fac997a246e59d943dd554af358a65Inhibition of Btk with CC-292 provides early pharmacodynamic assessment of activity in mice and humansEvans, Erica K.; Tester, Richland; Aslanian, Sharon; Karp, Russell; Sheets, Michael; Labenski, Matthew T.; Witowski, Steven R.; Lounsbury, Heather; Chaturvedi, Prasoon; Mazdiyasni, Hormoz; Zhu, Zhendong; Nacht, Mariana; Freed, Martin I.; Petter, Russell C.; Dubrovskiy, Alex; Singh, Juswinder; Westlin, William F.Journal of Pharmacology and Experimental Therapeutics (2013), 346 (2), 219-228CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)Targeted therapies that suppress B cell receptor (BCR) signaling have emerged as promising agents in autoimmune disease and B cell malignancies. Bruton's tyrosine kinase (Btk) plays a crucial role in B cell development and activation through the BCR signaling pathway and represents a new target for diseases characterized by inappropriate B cell activity. N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide (CC-292) is a highly selective, covalent Btk inhibitor and a sensitive and quant. assay that measures CC-292-Btk engagement has been developed. This translational pharmacodynamic assay has accompanied CC-292 through each step of drug discovery and development. These studies demonstrate the quantity of Btk bound by CC-292 correlates with the efficacy of CC-292 in vitro and in the collagen-induced arthritis model of autoimmune disease. Recently, CC-292 has entered human clin. trials with a trial design that has provided rapid insight into safety, pharmacokinetics, and pharmacodynamics. This first-in-human healthy volunteer trial has demonstrated that a single oral dose of 2 mg/kg CC-292 consistently engaged all circulating Btk protein and provides the basis for rational dose selection in future clin. trials. This targeted covalent drug design approach has enabled the discovery and early clin. development of CC-292 and has provided support for Btk as a valuable drug target for B-cell mediated disorders.
- 39Walter, H. S.; Rule, S. A.; Dyer, M. J.; Karlin, L.; Jones, C.; Cazin, B.; Quittet, P.; Shah, N.; Hutchinson, C. V.; Honda, H.; Duffy, K.; Birkett, J.; Jamieson, V.; Courtenay-Luck, N.; Yoshizawa, T.; Sharpe, J.; Ohno, T.; Abe, S.; Nishimura, A.; Cartron, G.; Morschhauser, F.; Fegan, C.; Salles, G. A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies. Blood 2016, 127, 411– 419, DOI: 10.1182/blood-2015-08-664086[Crossref], [PubMed], [CAS], Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1Cis7zO&md5=f12cd01520c82ddd2067f2b329bd38a9A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignanciesWalter, Harriet S.; Rule, Simon A.; Dyer, Martin J. S.; Karlin, Lionel; Jones, Ceri; Cazin, Bruno; Quittet, Philippe; Shah, Nimish; Hutchinson, Claire V.; Honda, Hideyuki; Duffy, Kevin; Birkett, Joseph; Jamieson, Virginia; Courtenay-Luck, Nigel; Yoshizawa, Toshio; Sharpe, John; Ohno, Tomoya; Abe, Shinichiro; Nishimura, Akihisa; Cartron, Guillaume; Morschhauser, Franck; Fegan, Christopher; Salles, GillesBlood (2016), 127 (4), 411-419CODEN: BLOOAW; ISSN:1528-0020. (American Society of Hematology)We report the results of a multicenter phase 1 dose-escalation study of the selective Bruton tyrosine kinase (BTK) inhibitor ONO/GS-4059 in 90 patients with relapsed/refractory B-cell malignancies. There were 9 dose-escalation cohorts ranging from 20 mg to 600 mg once daily with twice-daily regimens of 240 mg and 300 mg. Twenty-four of 25 evaluable chronic lymphocytic leukemia (CLL) patients (96%) responded to ONO/GS-4059, with a median treatment duration of 80 wk; 21 CLL patients remain on treatment. Lymph node responses were rapid and assocd. with a concurrent lymphocytosis. Eleven of 12 evaluable patients with mantle cell lymphoma (92%) responded (median treatment duration, 40 wk). Eleven of 31 non-germinal center B-cell diffuse large B-cell lymphoma patients (35%) responded but median treatment duration was 12 wk due to development of progressive disease. ONO/GS-4059 was very well tolerated with 75% of adverse events (AEs) being Common Toxicity Criteria for Adverse Events version 4.0 grade 1 or grade 2. Grade 3/4 AEs were mainly hematol. and recovered spontaneously during therapy. One CLL patient experienced a grade 3 treatment-related bleeding event (spontaneous muscle hematoma) but no clin. significant diarrhea, cardiac dysrhythmias, or arthralgia were obsd. No maximal tolerated dose (MTD) was reached in the CLL cohort. In the non-Hodgkin lymphoma cohort, 4 patients developed a dose-limiting toxicity, yielding an MTD of 480 mg once daily. ONO/GS-4059 has significant activity in relapsed/refractory B-cell malignancies without major drug-related toxicity. The selectivity of ONO/GS-4059 should confer advantages in combination therapies.
- 40Watterson, S. H.; Liu, Q.; Beaudoin Bertrand, M.; Batt, D. G.; Li, L.; Pattoli, M. A.; Skala, S.; Cheng, L.; Obermeier, M. T.; Moore, R.; Yang, Z.; Vickery, R.; Elzinga, P. A.; Discenza, L.; D’Arienzo, C.; Gillooly, K. M.; Taylor, T. L.; Pulicicchio, C.; Zhang, Y.; Heimrich, E.; McIntyre, K. W.; Ruan, Q.; Westhouse, R. A.; Catlett, I. M.; Zheng, N.; Chaudhry, C.; Dai, J.; Galella, M. A.; Tebben, A. J.; Pokross, M.; Li, J.; Zhao, R.; Smith, D.; Rampulla, R.; Allentoff, A.; Wallace, M. A.; Mathur, A.; Salter-Cid, L.; Macor, J. E.; Carter, P. H.; Fura, A.; Burke, J. R.; Tino, J. A. Discovery of branebrutinib (BMS-986195): a strategy for identifying a highly potent and selective covalent inhibitor providing rapid in vivo inactivation of Bruton’s tyrosine kinase (BTK). J. Med. Chem. 2019, 62, 3228– 3250, DOI: 10.1021/acs.jmedchem.9b00167[ACS Full Text], [CAS], Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXls1aks7w%253D&md5=2d521ec7c06d503f940cb44d381af58dDiscovery of Branebrutinib (BMS-986195): A Strategy for Identifying a Highly Potent and Selective Covalent Inhibitor Providing Rapid in Vivo Inactivation of Bruton's Tyrosine Kinase (BTK)Watterson, Scott H.; Liu, Qingjie; Beaudoin Bertrand, Myra; Batt, Douglas G.; Li, Ling; Pattoli, Mark A.; Skala, Stacey; Cheng, Lihong; Obermeier, Mary T.; Moore, Robin; Yang, Zheng; Vickery, Rodney; Elzinga, Paul A.; Discenza, Lorell; D'Arienzo, Celia; Gillooly, Kathleen M.; Taylor, Tracy L.; Pulicicchio, Claudine; Zhang, Yifan; Heimrich, Elizabeth; McIntyre, Kim W.; Ruan, Qian; Westhouse, Richard A.; Catlett, Ian M.; Zheng, Naiyu; Chaudhry, Charu; Dai, Jun; Galella, Michael A.; Tebben, Andrew J.; Pokross, Matt; Li, Jianqing; Zhao, Rulin; Smith, Daniel; Rampulla, Richard; Allentoff, Alban; Wallace, Michael A.; Mathur, Arvind; Salter-Cid, Luisa; Macor, John E.; Carter, Percy H.; Fura, Aberra; Burke, James R.; Tino, Joseph A.Journal of Medicinal Chemistry (2019), 62 (7), 3228-3250CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a crit. role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fcε receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacol. inhibition of BTK is anticipated to provide an effective strategy for the clin. treatment of autoimmune diseases such as rheumatoid arthritis and lupus. This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clin. studies.
- 41Angst, D.; Gessier, F.; Janser, P.; Vulpetti, A.; Walchli, R.; Beerli, C.; Littlewood-Evans, A.; Dawson, J.; Nuesslein-Hildesheim, B.; Wieczorek, G.; Gutmann, S.; Scheufler, C.; Hinniger, A.; Zimmerlin, A.; Funhoff, E. G.; Pulz, R.; Cenni, B. Discovery of LOU064 (Remibrutinib), a potent and highly selective covalent inhibitor of Bruton’s tyrosine kinase. J. Med. Chem. 2020, 63, 5102– 5118, DOI: 10.1021/acs.jmedchem.9b01916[ACS Full Text], [CAS], Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXjs1KiurY%253D&md5=9122b310c294d6071ae7cd73cdb91b3dDiscovery of LOU064 (Remibrutinib), a Potent and Highly Selective Covalent Inhibitor of Bruton's Tyrosine KinaseAngst, Daniela; Gessier, Francois; Janser, Philipp; Vulpetti, Anna; Walchli, Rudolf; Beerli, Christian; Littlewood-Evans, Amanda; Dawson, Janet; Nuesslein-Hildesheim, Barbara; Wieczorek, Grazyna; Gutmann, Sascha; Scheufler, Clemens; Hinniger, Alexandra; Zimmerlin, Alfred; Funhoff, Enrico G.; Pulz, Robert; Cenni, BrunoJournal of Medicinal Chemistry (2020), 63 (10), 5102-5118CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Bruton's tyrosine kinase (BTK), a cytoplasmic tyrosine kinase, plays a central role in immunity and is considered an attractive target for treating autoimmune diseases. The use of currently marketed covalent BTK inhibitors is limited to oncol. indications based on their suboptimal kinase selectivity. We describe the discovery and preclin. profile of LOU064 (remibrutinib, 25), a potent, highly selective covalent BTK inhibitor. LOU064 exhibits an exquisite kinase selectivity due to binding to an inactive conformation of BTK and has the potential for a best-in-class covalent BTK inhibitor for the treatment of autoimmune diseases. It demonstrates potent in vivo target occupancy with an EC90 of 1.6 mg/kg and dose-dependent efficacy in rat collagen-induced arthritis. LOU064 is currently being tested in phase 2 clin. studies for chronic spontaneous urticaria and Sjoegren's syndrome.
- 42Crawford, J. J.; Johnson, A. R.; Misner, D. L.; Belmont, L. D.; Castanedo, G.; Choy, R.; Coraggio, M.; Dong, L.; Eigenbrot, C.; Erickson, R.; Ghilardi, N.; Hau, J.; Katewa, A.; Kohli, P. B.; Lee, W.; Lubach, J. W.; McKenzie, B. S.; Ortwine, D. F.; Schutt, L.; Tay, S.; Wei, B.; Reif, K.; Liu, L.; Wong, H.; Young, W. B. Discovery of GDC-0853: a potent, selective, and noncovalent Bruton’s tyrosine kinase inhibitor in early clinical development. J. Med. Chem. 2018, 61, 2227– 2245, DOI: 10.1021/acs.jmedchem.7b01712[ACS Full Text], [CAS], Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXivFCnt7c%253D&md5=eddbd31f387fe86827a7469e8be45430Discovery of GDC-0853: A Potent, Selective, and Noncovalent Bruton's Tyrosine Kinase Inhibitor in Early Clinical DevelopmentCrawford, James J.; Johnson, Adam R.; Misner, Dinah L.; Belmont, Lisa D.; Castanedo, Georgette; Choy, Regina; Coraggio, Melis; Dong, Liming; Eigenbrot, Charles; Erickson, Rebecca; Ghilardi, Nico; Hau, Jonathan; Katewa, Arna; Kohli, Pawan Bir; Lee, Wendy; Lubach, Joseph W.; McKenzie, Brent S.; Ortwine, Daniel F.; Schutt, Leah; Tay, Suzanne; Wei, BinQing; Reif, Karin; Liu, Lichuan; Wong, Harvey; Young, Wendy B.Journal of Medicinal Chemistry (2018), 61 (6), 2227-2245CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Bruton's tyrosine kinase (Btk) is a nonreceptor cytoplasmic tyrosine kinase involved in B-cell and myeloid cell activation, downstream of B-cell and Fcγ receptors, resp. Preclin. studies have indicated that inhibition of Btk activity might offer a potential therapy in autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. Here we disclose the discovery and preclin. characterization of a potent, selective, and noncovalent Btk inhibitor currently in clin. development. GDC-0853 (29) suppresses B cell- and myeloid cell-mediated components of disease and demonstrates dose-dependent activity in an in vivo rat model of inflammatory arthritis. It demonstrates highly favorable safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles in preclin. and Phase 2 studies ongoing in patients with rheumatoid arthritis, lupus, and chronic spontaneous urticaria. On the basis of its potency, selectivity, long target residence time, and noncovalent mode of inhibition, 29 has the potential to be a best-in-class Btk inhibitor for a wide range of immunol. indications.
- 43Young, W. B.; Barbosa, J.; Blomgren, P.; Bremer, M. C.; Crawford, J. J.; Dambach, D.; Gallion, S.; Hymowitz, S. G.; Kropf, J. E.; Lee, S. H.; Liu, L.; Lubach, J. W.; Macaluso, J.; Maciejewski, P.; Maurer, B.; Mitchell, S. A.; Ortwine, D. F.; Di Paolo, J.; Reif, K.; Scheerens, H.; Schmitt, A.; Sowell, C. G.; Wang, X.; Wong, H.; Xiong, J. M.; Xu, J.; Zhao, Z.; Currie, K. S. Potent and selective Bruton’s tyrosine kinase inhibitors: discovery of GDC-0834. Bioorg. Med. Chem. Lett. 2015, 25, 1333– 1337, DOI: 10.1016/j.bmcl.2015.01.032[Crossref], [PubMed], [CAS], Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXisVSit7w%253D&md5=fdebc0199c8222e093cfb9583244bce3Potent and selective Bruton's tyrosine kinase inhibitors: Discovery of GDC-0834Young, Wendy B.; Barbosa, James; Blomgren, Peter; Bremer, Meire C.; Crawford, James J.; Dambach, Donna; Gallion, Steve; Hymowitz, Sarah G.; Kropf, Jeffrey E.; Lee, Seung H.; Liu, Lichuan; Lubach, Joseph W.; Macaluso, Jen; Maciejewski, Pat; Maurer, Brigitte; Mitchell, Scott A.; Ortwine, Daniel F.; Di Paolo, Julie; Reif, Karin; Scheerens, Heleen; Schmitt, Aaron; Sowell, C. Gregory; Wang, Xiaojing; Wong, Harvey; Xiong, Jin-Ming; Xu, Jianjun; Zhao, Zhongdong; Currie, Kevin S.Bioorganic & Medicinal Chemistry Letters (2015), 25 (6), 1333-1337CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)SAR studies focused on improving the pharmacokinetic (PK) properties of the previously reported potent and selective Btk inhibitor CGI-1746 resulted in the clin. candidate GDC-0834, which retained the potency and selectivity of CGI-1746, but with much improved PK in preclin. animal models. Structure based design efforts drove this work as modifications to CGI-1746 were investigated at both the solvent exposed region as well as 'H3 binding pocket'. However, in vitro metabolic evaluation of GDC-0834 revealed a non CYP-mediated metabolic process that was more prevalent in human than preclin. species (mouse, rat, dog, cyno), leading to a high-level of uncertainly in predicting human pharmacokinetics. Due to its promising potency, selectivity, and preclin. efficacy, a single dose IND was filed and GDC-0834 was taken in to a single dose phase I trial in healthy volunteers to quickly evaluate the human pharmacokinetics. In human, GDC-0834 was found to be highly labile at the exo-cyclic amide bond that links the tetrahydrobenzothiophene moiety to the central aniline ring, resulting in insufficient parent drug exposure. This information informed the back-up program and discovery of improved inhibitors.
- 44Herman, A. E.; Chinn, L. W.; Kotwal, S. G.; Murray, E. R.; Zhao, R.; Florero, M.; Lin, A.; Moein, A.; Wang, R.; Bremer, M.; Kokubu, S.; Serone, A. P.; Hanze, E. L.; Viberg, A.; Morimoto, A. M.; Winter, H. R.; Katsumoto, T. R. Safety, pharmacokinetics, and pharmacodynamics in healthy volunteers treated with GDC-0853, a selective reversible Bruton’s tyrosine kinase inhibitor. Clin. Pharmacol. Ther. 2018, 103, 1020– 1028, DOI: 10.1002/cpt.1056[Crossref], [PubMed], [CAS], Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVOqsrrK&md5=5384437ef44533ca18cd8f768ad853f3Safety, Pharmacokinetics, and Pharmacodynamics in Healthy Volunteers Treated With GDC-0853, a Selective Reversible Bruton's Tyrosine Kinase InhibitorHerman, Ann E.; Chinn, Leslie W.; Kotwal, Shweta G.; Murray, Elaine R.; Zhao, Rui; Florero, Marilyn; Lin, Alyse; Moein, Anita; Wang, Rena; Bremer, Meire; Kokubu, Serika; Serone, Adrian P.; Hanze, Eva L.; Viberg, Anders; Morimoto, Alyssa M.; Winter, Helen R.; Katsumoto, Tamiko R.Clinical Pharmacology & Therapeutics (Hoboken, NJ, United States) (2018), 103 (6), 1020-1028CODEN: CLPTAT; ISSN:0009-9236. (John Wiley & Sons, Inc.)GDC-0853 is a small mol. inhibitor of Bruton's tyrosine kinase (BTK) that is highly selective and noncovalent, leading to reversible binding. In double-blind, randomized, and placebo-controlled phase I healthy volunteer studies, GDC-0853 was well tolerated, with no dose-limiting adverse events (AEs) or serious AEs. The max. tolerated dose was not reached during dose escalation (≤ 600 mg, single ascending dose (SAD) study; ≤ 250 mg twice daily (b.i.d.) and ≤ 500 mg once daily, 14-day multiple ascending dose (MAD) study). Plasma concns. peaked 1-3 h after oral administration and declined thereafter, with a steady-state half-life ranging from 4.2-9.9 h. Independent assays demonstrated dose-dependent BTK target engagement. Based on pharmacokinetic/pharmacodynamic (PK/PD) simulations, a once-daily dosing regimen (e.g., 100 mg, q.d.) is expected to maintain a high level of BTK inhibition over the dosing interval. Taken together, the safety and PK/PD data support GDC-0853 evaluation in rheumatoid arthritis, lupus, and other autoimmune or inflammatory indications.
- 45Byrd, J. C.; Smith, S.; Wagner-Johnston, N.; Sharman, J.; Chen, A. I.; Advani, R.; Augustson, B.; Marlton, P.; Renee Commerford, S.; Okrah, K.; Liu, L.; Murray, E.; Penuel, E.; Ward, A. F.; Flinn, I. W. First-in-human phase 1 study of the BTK inhibitor GDC-0853 in relapsed or refractory B-cell NHL and CLL. Oncotarget 2018, 9, 13023– 13035, DOI: 10.18632/oncotarget.24310[Crossref], [PubMed], [CAS], Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1Mnjt1Srug%253D%253D&md5=6fa90aae6c292025323e7eef768e93cfFirst-in-human phase 1 study of the BTK inhibitor GDC-0853 in relapsed or refractory B-cell NHL and CLLByrd John C; Smith Stephen; Wagner-Johnston Nina; Sharman Jeff; Chen Andy I; Advani Ranjana; Augustson Bradley; Marlton Paula; Renee Commerford S; Okrah Kwame; Liu Lichuan; Murray Elaine; Penuel Elicia; Ward Ashley F; Flinn Ian WOncotarget (2018), 9 (16), 13023-13035 ISSN:.GDC-0853 is a selective, reversible, and non-covalent inhibitor of Bruton's tyrosine kinase (BTK) that does not require interaction with the Cys481 residue for activity. In this first-in-human phase 1 study we evaluated safety, tolerability, pharmacokinetics, and activity of GDC-0853 in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL). Twenty-four patients, enrolled into 3 cohorts, including 6 patients who were positive for the C481S mutation, received GDC-0853 at 100, 200, or 400 mg once daily, orally. There were no dose limiting toxicities. GDC-0853 was well tolerated and the maximum tolerated dose (MTD) was not reached due to premature study closure. Common adverse events (AEs) in ≥ 15% of patients regardless of causality included fatigue (37%), nausea (33%), diarrhea (29%), thrombocytopenia (25%), headache (20%), and abdominal pain, cough, and dizziness (16%, each). Nine serious AEs were reported in 5 patients of whom 2 had fatal outcomes (confirmed H1N1 influenza and influenza pneumonia). A third death was due to progressive disease. Eight of 24 patients responded to GDC-0853: 1 complete response, 4 partial responses, and 3 partial responses with lymphocytosis, including 1 patient with the C481S mutation. Two additional C481S mutation patients had a decrease in size of target tumors (-23% and -44%). These data demonstrate GDC-0853 was generally well-tolerated with antitumor activity.
- 46Watterson, S. H.; De Lucca, G. V.; Shi, Q.; Langevine, C. M.; Liu, Q.; Batt, D. G.; Beaudoin Bertrand, M.; Gong, H.; Dai, J.; Yip, S.; Li, P.; Sun, D.; Wu, D.-R.; Wang, C.; Zhang, Y.; Traeger, S. C.; Pattoli, M. A.; Skala, S.; Cheng, L.; Obermeier, M. T.; Vickery, R.; Discenza, L. N.; D’Arienzo, C. J.; Zhang, Y.; Heimrich, E.; Gillooly, K. M.; Taylor, T. L.; Pulicicchio, C.; McIntyre, K. W.; Galella, M. A.; Tebben, A. J.; Muckelbauer, J. K.; Chang, C.; Rampulla, R.; Mathur, A.; Salter-Cid, L.; Barrish, J. C.; Carter, P. H.; Fura, A.; Burke, J. R.; Tino, J. A. Discovery of 6-fluoro-5-(r)-(3-(s)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4h)-yl)-2-methylphenyl)-2-(s)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8- carboxamide (BMS-986142): a reversible inhibitor of Bruton’s tyrosine kinase (BTK) conformationally constrained by two locked atropisomers. J. Med. Chem. 2016, 59, 9173– 9200, DOI: 10.1021/acs.jmedchem.6b01088[ACS Full Text], [CAS], Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVKjsrfF&md5=91098abc802521b9ad91563d20ac5893Discovery of 6-Fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (BMS-986142): A Reversible Inhibitor of Bruton's Tyrosine Kinase (BTK) Conformationally Constrained by Two Locked AtropisomersWatterson, Scott H.; De Lucca, George V.; Shi, Qing; Langevine, Charles M.; Liu, Qingjie; Batt, Douglas G.; Beaudoin Bertrand, Myra; Gong, Hua; Dai, Jun; Yip, Shiuhang; Li, Peng; Sun, Dawn; Wu, Dauh-Rurng; Wang, Chunlei; Zhang, Yingru; Traeger, Sarah C.; Pattoli, Mark A.; Skala, Stacey; Cheng, Lihong; Obermeier, Mary T.; Vickery, Rodney; Discenza, Lorell N.; D'Arienzo, Celia J.; Zhang, Yifan; Heimrich, Elizabeth; Gillooly, Kathleen M.; Taylor, Tracy L.; Pulicicchio, Claudine; McIntyre, Kim W.; Galella, Michael A.; Tebben, Andy J.; Muckelbauer, Jodi K.; Chang, ChiehYing; Rampulla, Richard; Mathur, Arvind; Salter-Cid, Luisa; Barrish, Joel C.; Carter, Percy H.; Fura, Aberra; Burke, James R.; Tino, Joseph A.Journal of Medicinal Chemistry (2016), 59 (19), 9173-9200CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcγ receptor signaling in monocytes and Fcε receptor signaling in mast cells and basophils, all of which have been implicated in the pathophysiol. of autoimmune disease. As a result, inhibition of BTK is anticipated to provide an effective strategy for the clin. treatment of autoimmune diseases such as lupus and rheumatoid arthritis. This article details the structure-activity relationships (SAR) leading to a novel series of highly potent and selective carbazole and tetrahydrocarbazole based, reversible inhibitors of BTK. Of particular interest is that two atropisomeric centers were rotationally locked to provide a single, stable atropisomer, resulting in enhanced potency and selectivity as well as a redn. in safety liabilities. With significantly enhanced potency and selectivity, excellent in vivo properties and efficacy, and a very desirable tolerability and safety profile, 14f (BMS-986142) was advanced into clin. studies.
- 47Lee, S. K.; Xing, J.; Catlett, I. M.; Adamczyk, R.; Griffies, A.; Liu, A.; Murthy, B.; Nowak, M. Safety, pharmacokinetics, and pharmacodynamics of BMS-986142, a novel reversible BTK inhibitor, in healthy participants. Eur. J. Clin. Pharmacol. 2017, 73, 689– 698, DOI: 10.1007/s00228-017-2226-2[Crossref], [PubMed], [CAS], Google Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjvVahs70%253D&md5=d1435ec2479d5a50d0a5b863cc98d803Safety, pharmacokinetics, and pharmacodynamics of BMS-986142, a novel reversible BTK inhibitor, in healthy participantsLee, Sun Ku; Xing, Jun; Catlett, Ian M.; Adamczyk, Robert; Griffies, Amber; Liu, Ang; Murthy, Bindu; Nowak, MiroslawaEuropean Journal of Clinical Pharmacology (2017), 73 (6), 689-698CODEN: EJCPAS; ISSN:0031-6970. (Springer)BMS-986142 is an oral, small-mol. reversible inhibitor of Bruton's tyrosine kinase. The main objectives of our phase I studies were to characterize the safety and tolerability, pharmacokinetics, and pharmacodynamics of BMS-986142 in healthy participants, and to investigate the potential for the effect of BMS-986142 on the PK of methotrexate (MTX) in combination. In a combined single ascending dose and multiple ascending dose study, the safety, pharmacokinetics, and pharmacodynamics of BMS-986142 were assessed in healthy non-Japanese participants following administration of a single dose (5-900 mg) or multiple doses (25-350 mg, once daily for 14 days). In a drug-drug interaction study, the effect of BMS-986142 (350 mg, once daily for 5 days) on the single-dose pharmacokinetics of MTX (7.5 mg) was assessed in healthy participants. Results: BMS-986142 was generally well tolerated, alone and in combination with MTX. BMS-986142 was rapidly absorbed with peak concns. occurring within 2 h, and was eliminated with a mean half-life ranging from 7 to 11 h. Exposure of BMS-986142 appeared dose proportional within the dose ranges tested. A dose- and concn.-dependent inhibition of CD69 expression was obsd. following administration of BMS-986142. BMS-986142 did not affect the pharmacokinetics of MTX. BMS-986142 was well tolerated at the doses tested, had pharmacokinetic and pharmacodynamic profiles which support once-daily dosing, and can be coadministered with MTX without the pharmacokinetic interaction of BMS-986142 on MTX.
- 48Lou, Y.; Han, X.; Kuglstatter, A.; Kondru, R. K.; Sweeney, Z. K.; Soth, M.; McIntosh, J.; Litman, R.; Suh, J.; Kocer, B.; Davis, D.; Park, J.; Frauchiger, S.; Dewdney, N.; Zecic, H.; Taygerly, J. P.; Sarma, K.; Hong, J.; Hill, R. J.; Gabriel, T.; Goldstein, D. M.; Owens, T. D. Structure-based drug design of RN486, a potent and selective Bruton’s tyrosine kinase (BTK) inhibitor, for the treatment of rheumatoid arthritis. J. Med. Chem. 2015, 58, 512– 516, DOI: 10.1021/jm500305p[ACS Full Text], [CAS], Google Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXlsl2qtb8%253D&md5=dc3c069b0e876f44846a30e3aa6a894aStructure-Based Drug Design of RN486, a Potent and Selective Bruton's Tyrosine Kinase (BTK) Inhibitor, for the Treatment of Rheumatoid ArthritisLou, Yan; Han, Xiaochun; Kuglstatter, Andreas; Kondru, Rama K.; Sweeney, Zachary K.; Soth, Michael; McIntosh, Joel; Litman, Renee; Suh, Judy; Kocer, Buelent; Davis, Dana; Park, Jaehyeon; Frauchiger, Sandra; Dewdney, Nolan; Zecic, Hasim; Taygerly, Joshua P.; Sarma, Keshab; Hong, Junbae; Hill, Ronald J.; Gabriel, Tobias; Goldstein, David M.; Owens, Timothy D.Journal of Medicinal Chemistry (2015), 58 (1), 512-516CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alc. group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compd. I (RN486) (J. Pharmacol. Exp. Ther. 2012, 341, 90), which was selected for advanced preclin. characterization based on its favorable properties.
- 49Smith, C. R.; Dougan, D. R.; Komandla, M.; Kanouni, T.; Knight, B.; Lawson, J. D.; Sabat, M.; Taylor, E. R.; Vu, P.; Wyrick, C. Fragment-based discovery of a small molecule inhibitor of Bruton’s tyrosine kinase. J. Med. Chem. 2015, 58, 5437– 5444, DOI: 10.1021/acs.jmedchem.5b00734[ACS Full Text], [CAS], Google Scholar49https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVans7rF&md5=d6626fabcc3e2aa6a9180dc702a5030cFragment-Based Discovery of a Small Molecule Inhibitor of Bruton's Tyrosine KinaseSmith, Christopher R.; Dougan, Douglas R.; Komandla, Mallareddy; Kanouni, Toufike; Knight, Beverly; Lawson, J. David; Sabat, Mark; Taylor, Ewan R.; Vu, Phong; Wyrick, CoreyJournal of Medicinal Chemistry (2015), 58 (14), 5437-5444CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The discovery and optimization of a series of 4-aminocinnoline-3-carboxamide inhibitors of Bruton's tyrosine kinase are reported. A fragment-based screening approach incorporating x-ray cocrystallog. was used to identify a cinnoline fragment and characterize its binding mode in the ATP binding site of Btk. Optimization of the fragment hit resulted in the identification of a lead compd. I which reduced paw swelling in a dose- and exposure-dependent fashion in a rat model of collagen-induced arthritis.
- 50Kawahata, W.; Asami, T.; Kiyoi, T.; Irie, T.; Taniguchi, H.; Asamitsu, Y.; Inoue, T.; Miyake, T.; Sawa, M. Design and synthesis of novel amino-triazine analogues as selective Bruton’s tyrosine kinase inhibitors for treatment of rheumatoid arthritis. J. Med. Chem. 2018, 61, 8917– 8933, DOI: 10.1021/acs.jmedchem.8b01147[ACS Full Text], [CAS], Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslaitLbK&md5=56afc013f74a2912624c57c61a197845Design and Synthesis of Novel Amino-triazine Analogues as Selective Bruton's Tyrosine Kinase Inhibitors for Treatment of Rheumatoid ArthritisKawahata, Wataru; Asami, Tokiko; Kiyoi, Takao; Irie, Takayuki; Taniguchi, Haruka; Asamitsu, Yuko; Inoue, Tomoko; Miyake, Takahiro; Sawa, MasaakiJournal of Medicinal Chemistry (2018), 61 (19), 8917-8933CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Bruton's tyrosine kinase (BTK) is a promising drug target for the treatment of multiple diseases, such as B-cell malignances, asthma, and rheumatoid arthritis. A series of novel aminotriazines were identified as highly selective inhibitors of BTK by a scaffold-hopping approach. Subsequent SAR studies of this series using two conformationally different BTK proteins, an activated form of BTK and an unactivated form of BTK, led to the discovery of a highly selective BTK inhibitor, I. With significant efficacy in models in vivo and good ADME and safety profiles, I was advanced into preclin. studies.
- 51Yao, X.; Sun, X.; Jin, S.; Yang, L.; Xu, H.; Rao, Y. Discovery of 4-aminoquinoline-3-carboxamide derivatives as potent reversible Bruton’s tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. J. Med. Chem. 2019, 62, 6561– 6574, DOI: 10.1021/acs.jmedchem.9b00329[ACS Full Text], [CAS], Google Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtlamsrvF&md5=1eca629234ee9e3b95e1497526851e2aDiscovery of 4-Aminoquinoline-3-carboxamide Derivatives as Potent Reversible Bruton's Tyrosine Kinase Inhibitors for the Treatment of Rheumatoid ArthritisYao, Xia; Sun, Xiuyun; Jin, Shuyu; Yang, Ling; Xu, Hongjiang; Rao, YuJournal of Medicinal Chemistry (2019), 62 (14), 6561-6574CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A structure-hopping strategy was applied to discover a series of novel 4-aminoquinoline-3-carboxamide derivs. as potent, reversible BTK inhibitors. Compared to the previously described cinnoline scaffold compds., the 4-aminoquinoline analogs showed significantly improved drug-like properties, esp. in their aq. soly. The most potent compd., 25, displayed a stronger inhibitory effect on both BTKWT (IC50 = 5.3 nM) and BTKC481S (IC50 = 39 nM). In a rodent collagen-induced arthritis model, compd. 25 efficiently reduced paw swelling without a loss in body wt. On the basis of potency, drug-like properties, stability, and noncovalent mode of inhibition, our representative inhibitors could have a promising profile to be treatments for a wide range of autoimmune diseases.
- 52Amano, M.; Nakayama, M.; Kaibuchi, K. Rho-kinase/ROCK: A key regulator of the cytoskeleton and cell polarity. Cytoskeleton 2010, 67, 545– 554, DOI: 10.1002/cm.20472[Crossref], [CAS], Google Scholar52https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFOrs7vM&md5=fa704bca66855ebd20461a3410580ed4Rho-kinase/ROCK: a key regulator of the cytoskeleton and cell polarityAmano, Mutsuki; Nakayama, Masanori; Kaibuchi, KozoCytoskeleton (2010), 67 (9), 545-554CODEN: CYTOBO; ISSN:1949-3584. (Wiley-Blackwell)A review. Rho-assocd. kinase (Rho-kinase/ROCK/ROK) is an effector of the small GTPase Rho and belongs to the AGC family of kinases. Rho-kinase has pleiotropic functions including the regulation of cellular contraction, motility, morphol., polarity, cell division, and gene expression. Pharmacol. analyses have revealed that Rho-kinase is involved in a wide range of diseases such as vasospasm, pulmonary hypertension, nerve injury, and glaucoma, and is therefore considered to be a potential therapeutic target. This review focuses on the structure, function, and modes of activation and action of Rho-kinase.
- 53Feng, Y. B.; LoGrasso, P. V.; Defert, O.; Li, R. S. Rho kinase (ROCK) inhibitors and their therapeutic potential. J. Med. Chem. 2016, 59, 2269– 2300, DOI: 10.1021/acs.jmedchem.5b00683[ACS Full Text], [CAS], Google Scholar53https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1Oqtb%252FJ&md5=99b0e10dca303023b1bf382fcb255771Rho Kinase (ROCK) Inhibitors and Their Therapeutic PotentialFeng, Yangbo; LoGrasso, Philip V.; Defert, Olivier; Li, RongshiJournal of Medicinal Chemistry (2016), 59 (6), 2269-2300CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Rho kinases (ROCKs) belong to the serine-threonine family, the inhibition of which affects the function of many downstream substrates. As such, ROCK inhibitors have potential therapeutic applicability in a wide variety of pathol. conditions including asthma, cancer, erectile dysfunction, glaucoma, insulin resistance, kidney failure, neuronal degeneration, and osteoporosis. To date, two ROCK inhibitors have been approved for clin. use in Japan (fasudil and ripasudil) and one in China (fasudil). In 1995 fasudil was approved for the treatment of cerebral vasospasm, and more recently, ripasudil was approved for the treatment of glaucoma in 2014. In this Perspective, we present a comprehensive review of the physiol. and biol. functions for ROCK, the properties and development of over 170 ROCK inhibitors as well as their therapeutic potential, the current status, and future considerations.
- 54Nourinia, R.; Nakao, S.; Zandi, S.; Safi, S.; Hafezi-Moghadam, A.; Ahmadieh, H. ROCK inhibitors for the treatment of ocular diseases. Br. J. Ophthalmol. 2018, 102, 1– 5, DOI: 10.1136/bjophthalmol-2017-310378
- 55Lin, C. W.; Sherman, B.; Moore, L. A.; Laethem, C. L.; Lu, D. W.; Pattabiraman, P. P.; Rao, P. V.; deLong, M. A.; Kopczynski, C. C. Discovery and preclinical development of netarsudil, a novel ocular hypotensive agent for the treatment of glaucoma. J. Ocul. Pharmacol. Ther. 2018, 34, 40– 51, DOI: 10.1089/jop.2017.0023[Crossref], [PubMed], [CAS], Google Scholar55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXivFCns7w%253D&md5=0aab049b2ff35df0ce0f03b33bb5f501Discovery and Preclinical Development of Netarsudil, a Novel Ocular Hypotensive Agent for the Treatment of GlaucomaLin, Cheng-Wen; Sherman, Bryan; Moore, Lori A.; Laethem, Carmen L.; Lu, Da-Wen; Pattabiraman, Padmanabhan P.; Rao, Ponugoti Vasantha; de Long, Mitchell A.; Kopczynski, Casey C.Journal of Ocular Pharmacology and Therapeutics (2018), 34 (1-2), 40-51CODEN: JOPTFU; ISSN:1080-7683. (Mary Ann Liebert, Inc.)Purpose: Rho-assocd. protein kinase (ROCK) inhibitors lower intraocular pressure (IOP) by increasing aq. outflow through the trabecular meshwork (TM). The preclin. characterization of netarsudil, a new ROCK/norepinephrine transporter (NET) inhibitor currently in clin. development, is presented herein. Methods: The kinase inhibitory activity of netarsudil was compared to its esterase metabolite, netarsudil-M1, and 3 other ROCK inhibitors using a com. available kinase assay kit. Disruption of actin stress fibers was measured in primary porcine TM cells and disruption of focal adhesions in transformed human TM (HTM) cells. Induction of fibrosis markers after exposure to transforming growth factor-β2 (TGF-β2) was conducted in primary HTM cells. Ocular hypotensive activity and tolerability of topical formulations were evaluated in normotensive Dutch Belted rabbits and Formosan Rock monkeys. In vitro corneal metab. assays were conducted using dog, pig, rabbit, monkey, and human corneas. In vivo ocular pharmacokinetics was studied in Dutch Belted rabbits. Results: Netarsudil inhibited kinases ROCK1 and ROCK2 with a Ki of 1 nM each, disrupted actin stress fibers and focal adhesions in TM cells with IC50s of 79 and 16 nM, resp., and blocked the profibrotic effects of TGF-β2 in HTM cells. Netarsudil produced large redns. in IOP in rabbits and monkeys that were sustained for at least 24 h after once daily dosing, with transient, mild hyperemia obsd. as the only adverse effect. Conclusion: Netarsudil is a novel ROCK/NET inhibitor with high potency in biochem. and cell-based assays, an ability to produce large and durable IOP redns. in animal models, and favorable pharmacokinetic and ocular tolerability profiles.
- 56Nagumo, H.; Sasaki, Y.; Ono, Y.; Okamoto, H.; Seto, M.; Takuwa, Y. Rho kinase inhibitor HA-1077 prevents Rho-mediated myosin phosphatase inhibition in smooth muscle cells. Am. J. Physiol Cell Physiol 2000, 278, C57– 65, DOI: 10.1152/ajpcell.2000.278.1.C57
- 57Yamaguchi, H.; Kasa, M.; Amano, M.; Kaibuchi, K.; Hakoshima, T. Molecular mechanism for the regulation of rho-kinase by dimerization and its inhibition by fasudil. Structure 2006, 14, 589– 600, DOI: 10.1016/j.str.2005.11.024[Crossref], [PubMed], [CAS], Google Scholar57https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xit1ylt78%253D&md5=c00104ab0fe7731e51b68b3762ee894aMolecular Mechanism for the Regulation of Rho-Kinase by Dimerization and Its Inhibition by FasudilYamaguchi, Hiroto; Kasa, Miyuki; Amano, Mutsuki; Kaibuchi, Kozo; Hakoshima, ToshioStructure (Cambridge, MA, United States) (2006), 14 (3), 589-600CODEN: STRUE6; ISSN:0969-2126. (Cell Press)Rho-kinase is a key regulator of cytoskeletal events and a promising drug target in the treatment of vascular diseases and neurol. disorders. Unlike other protein kinases, Rho-kinase requires both N- and C-terminal extension segments outside the kinase domain for activity, although the details of this requirement have been elusive. The crystal structure of an active Rho-kinase fragment contg. the kinase domain and both the extensions revealed a head-to-head homodimer through the N-terminal extension forming a helix bundle that structurally integrates the C-terminal extension. This structural organization enables binding of the C-terminal hydrophobic motif to the N-terminal lobe, which defines the correct disposition of helix αC that is important for the catalytic activity. The bound inhibitor fasudil significantly alters the conformation and, consequently, the mode of interaction with the catalytic cleft that contains local structural changes. Thus, both kinase and drug conformational pliability and stability confer selectivity.
- 58Raja, S. G. Evaluation of clinical efficacy of fasudil for the treatment of pulmonary arterial hypertension. Recent Pat. Cardiovasc. Drug Discovery 2012, 7, 100– 104, DOI: 10.2174/157489012801227238[Crossref], [PubMed], [CAS], Google Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVOqsLrF&md5=8ffecab28efd9a852eabb916f93b834bEvaluation of clinical efficacy of fasudil for the treatment of pulmonary arterial hypertensionRaja, Shahzad G.Recent Patents on Cardiovascular Drug Discovery (2012), 7 (2), 100-104CODEN: RPCDFC; ISSN:1574-8901. (Bentham Science Publishers Ltd.)A review. Multiple cell types in the vascular wall rely upon the rho-kinase (ROCK) signaling pathway for homeostatic function and response to injury. These cell types include endothelial and vascular smooth muscle cells, inflammatory cells, and fibroblasts. Rho is a guanosine triphosphate binding protein that activates its downstream target rho-kinase, in response to activation of a variety of G-protein coupled receptors. When activated, ROCK inhibits myosin phosphatase and conversely upregulates the ezrin-radixin-moesin family of kinases. In vitro activation of these signaling cascades results in modulation of multiple cellular processes, including enhanced vasoconstriction, proliferation, impaired endothelial response to vasodilators, chronic pulmonary remodeling, and upregulation of vasoactive cytokines via the NF-κB transcription pathway. ROCK activity has also been linked specifically to a no. of known effectors of pulmonary arterial hypertension (PAH), including endothelin-1, serotonin, and endothelial nitric oxide synthase, among others. Recently, elevated ROCK activity has been demonstrated in various animal models of PAH with ROCK inhibitors assocd. with pulmonary vasodilatation and regression of PAH. ROCK inhibitors are a new class of agents which may be beneficial in the treatment of PAH. Fasudil (Daiichi Chem. and Pharmacol. Company, Ibaragi, Japan), a first generation ROCK inhibitor, has been widely studied. Emerging evidence from both animal and human studies suggests that fasudil can promote vasodilation independent of the mechanism that induces vasoconstriction and will be useful in conditions in which endothelial function is impaired including PAH. Several recent patents have described fasudil as a potential therapeutic option in PAH. This article provides an overview of the role of ROCK in the pathogenesis of PAH and discusses the clin. efficacy of fasudil as a therapeutic option for treating PAH.
- 59Garnock-Jones, K. P. Ripasudil: first global approval. Drugs 2014, 74, 2211– 2215, DOI: 10.1007/s40265-014-0333-2[Crossref], [PubMed], [CAS], Google Scholar59https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvF2htrzL&md5=e87121e469a273b2f95f9e4011dfea71Ripasudil: First Global ApprovalGarnock-Jones, Karly P.Drugs (2014), 74 (18), 2211-2215CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)A review. Ripasudil hydrochloride hydrate (Glanatec ophthalmic soln. 0.4 %; hereafter referred to as ripasudil) is a small-mol., Rho-assocd. kinase inhibitor developed by Kowa Company, Ltd. for the treatment of glaucoma and ocular hypertension. This compd., which was originally discovered by D. Western Therapeutics Institute, Inc., reduces intraocular pressure (IOP) by directly acting on the trabecular meshwork, thereby increasing conventional outflow through the Schlemm's canal. As a result of this mechanism of action, ripasudil may offer additive effects in the treatment of glaucoma and ocular hypertension when used in combination with agents such as prostaglandin analogs (which increase uveoscleral outflow) and β blockers (which reduce aq. prodn.). The eye drop product has been approved in Japan for the twice-daily treatment of glaucoma and ocular hypertension, when other therapeutic agents are not effective or cannot be administered. Phase II study is underway for the treatment of diabetic retinopathy. This article summarizes the milestones in the development of ripasudil leading to the first approval for glaucoma and ocular hypertension.
- 60Okumura, N.; Okazaki, Y.; Inoue, R.; Kakutani, K.; Nakano, S.; Kinoshita, S.; Koizumi, N. Effect of the rho-associated kinase inhibitor eye drop (Ripasudil) on corneal endothelial wound healing. Invest. Ophthalmol. Visual Sci. 2016, 57, 1284– 1292, DOI: 10.1167/iovs.15-18586[Crossref], [PubMed], [CAS], Google Scholar60https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XpvVaqur4%253D&md5=51a3e580b0b118d22558bc026a5909b2Effect of the rho-associated kinase inhibitor eye drop (ripasudil) on corneal endothelial wound healingOkumura, Naoki; Okazaki, Yugo; Inoue, Ryota; Kakutani, Kazuya; Nakano, Shinichiro; Kinoshita, Shigeru; Koizumi, NorikoInvestigative Ophthalmology & Visual Science (2016), 57 (3), 1284-1292CODEN: IOVSDA; ISSN:1552-5783. (Association for Research in Vision and Ophthalmology)PURPOSE. Ripasudil (Glanatec), a selective rho-assocd. coiled coil-contg. protein kinase (ROCK) inhibitor, was approved as a glaucoma and ocular hypertension treatment in Japan in 2014. The purpose of this study was to investigate the feasibility of using ripasudil eye drops to treat corneal endothelial injuries. METHODS. Cultured human corneal endothelial cells (HCECs) were treated with ripasudil, and 5-bromo-2'-deoxyuridine (BrdU) incorporation was evaluated by ELISA. A rabbit corneal endothelial damage model was also created by mech. scraping the corneal endothelium, followed by topical ripasudil eye drop application for 2 wk. The anterior segment was evaluated by slit-lamp microscopy, and central corneal thickness was measured by ultrasound pachymetry. Corneal specimens were evaluated by phalloidin staining and immunohistochem. anal. using antibodies against Ki67, N-cadherin, and Na+/K+-ATPase. RESULTS. Many more BrdU-pos. cells were obsd. among the HCECs treated with ripasudil (0.3-30 μM) than among the control HCECs. Ripasudil-treated eyes in a rabbit model showed 91.5 ± 2.0% Ki67-pos. cells after 48 h, whereas control eyes showed 52.6 ± 1.3%. Five of six corneas became transparent in ripasudil-treated eyes, whereas zero of six corneas became transparent in the control eyes. Regenerated cell densities were higher in the eyes treated with ripasudil than in eyes treated with vehicle. Eyes treated with ripasudil expressed N-cadherin and Na+/K+-ATPase in almost all CECs, whereas this expression was decreased in control eyes. CONCLUSIONS. Ripasudil promoted corneal endothelial wound healing, supporting its development as eye drops for treating acute corneal endothelial damage due to eye surgeries, esp. cataract surgery.
- 61Futakuchi, A.; Inoue, T.; Fujimoto, T.; Inoue-Mochita, M.; Kawai, M.; Tanihara, H. The effects of ripasudil (K-115), a Rho kinase inhibitor, on activation of human conjunctival fibroblasts. Exp. Eye Res. 2016, 149, 107– 115, DOI: 10.1016/j.exer.2016.07.001[Crossref], [PubMed], [CAS], Google Scholar61https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFyhtrjP&md5=ab32c0a37390d169f6675c1364e38534The effects of ripasudil (K-115), a Rho kinase inhibitor, on activation of human conjunctival fibroblastsFutakuchi, Akiko; Inoue, Toshihiro; Fujimoto, Tomokazu; Inoue-Mochita, Miyuki; Kawai, Motofumi; Tanihara, HidenobuExperimental Eye Research (2016), 149 (), 107-115CODEN: EXERA6; ISSN:0014-4835. (Elsevier Ltd.)The most common cause of glaucoma surgery failure is scar formation induced by activation of wound-healing responses and resultant fibrosis at the surgical site. We investigated the effects of ripasudil, a Rho kinase inhibitor, on activation of human conjunctival fibroblasts (HConF). HConF were pretreated with different concns. of ripasudil for 1 h before addn. of transforming growth factor (TGF)-β2, followed by incubation for 48 h. TGF-β2-treated fibroblasts exhibited a significant increase in expression of α-smooth muscle actin (α-SMA), a marker of fibroblast-to-myofibroblast differentiation, and this increase was significantly suppressed, in a dose-dependent manner, by pretreatment with ripasudil. Ripasudil pretreatment also significantly attenuated TGF-β2-induced fibronectin prodn. and collagen gel contraction. TGF-β2 increased both the no. of viable cells and the no. of cells in the G2/M phase of the cell cycle; these effects were attenuated by pretreatment with ripasudil. In addn., we explored the effects of ripasudil on stimulation of HConF by activated macrophages. Human monocytic cell line THP-1 cells were differentiated into M1 or M2 macrophage-like cells, and HConF were treated with conditioned media derived from these macrophages in the presence or absence of ripasudil. Conditioned medium from M2 macrophage-like cells induced a significant increase in α-SMA expression, viable cell nos., and gel contraction, all of which were significantly suppressed by ripasudil. Thus, overall, ripasudil attenuated activation of human conjunctival fibroblasts. Ripasudil may be of therapeutic utility, preventing excessive scarring after glaucoma filtration surgery.
- 62Nakata, J.; Akiba, Y.; Nihara, J.; Thant, L.; Eguchi, K.; Kato, H.; Izumi, K.; Ohkura, M.; Otake, M.; Kakihara, Y.; Saito, I.; Saeki, M. ROCK inhibitors enhance bone healing by promoting osteoclastic and osteoblastic differentiation. Biochem. Biophys. Res. Commun. 2020, 526, 547– 552, DOI: 10.1016/j.bbrc.2020.03.033[Crossref], [PubMed], [CAS], Google Scholar62https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXlt1Wls7o%253D&md5=e625e2f9e50d2b4b03c4739a52e54b41ROCK inhibitors enhance bone healing by promoting osteoclastic and osteoblastic differentiationNakata, Juri; Akiba, Yosuke; Nihara, Jun; Thant, Lay; Eguchi, Kaori; Kato, Hiroko; Izumi, Kenji; Ohkura, Mariko; Otake, Masanori; Kakihara, Yoshito; Saito, Isao; Saeki, MakioBiochemical and Biophysical Research Communications (2020), 526 (3), 547-552CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)Osteoclast and osteoblast are essential for proper bone development and remodeling as well as recovery of bone fracture. In this study, we seek chem. compds. that enhance turnover of bone metab. for promoting bone healing. First, we screen a chem. library which includes 378 compds. by using murine pre-osteoclastic RAW264.7 cells to identify compds. that promote osteoclastic differentiation. We find that two ROCK (Rho-assocd. coiled-coil kinase) inhibitors, HA-1077 (Fasudil) and Y-27632, enhance osteoclastogenesis. Subsequently, we identify that these two compds. also increase osteoblastic differentiation of MC3T3-E1 cells. Finally, our in vivo expt. shows that the local administration of ROCK inhibitors accelerate the bone healing of the rat calvarial defect.
- 63Hamano, T.; Shirafuji, N.; Yen, S. H.; Yoshida, H.; Kanaan, N. M.; Hayashi, K.; Ikawa, M.; Yamamura, O.; Fujita, Y.; Kuriyama, M.; Nakamoto, Y. Rho-kinase ROCK inhibitors reduce oligomeric tau protein. Neurobiol. Aging 2020, 89, 41– 54, DOI: 10.1016/j.neurobiolaging.2019.12.009[Crossref], [PubMed], [CAS], Google Scholar63https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXjtlaqtA%253D%253D&md5=7832dbe09c9eebec1e5fcfd32aaed826Rho-kinase ROCK inhibitors reduce oligomeric tau proteinHamano, Tadanori; Shirafuji, Norimichi; Yen, Shu-Hui; Yoshida, Hirotaka; Kanaan, Nicholas M.; Hayashi, Kouji; Ikawa, Masamichi; Yamamura, Osamu; Fujita, Youshi; Kuriyama, Masaru; Nakamoto, YasunariNeurobiology of Aging (2020), 89 (), 41-54CODEN: NEAGDO; ISSN:0197-4580. (Elsevier)Neurofibrillary tangles, one of the pathol. hallmarks of Alzheimer's disease, consist of highly phosphorylated tau proteins. Tau protein binds to microtubules and is best known for its role in regulating microtubule dynamics. However, if tau protein is phosphorylated by activated major tau kinases, including glycogen synthase kinase 3β or cyclin-dependent kinase 5, or inactivated tau phosphatase, including protein phosphatase 2A, its affinity for microtubules is reduced, and the free tau is believed to aggregate, thereby forming neurofibrillary tangles. We previously reported that pitavastatin decreases the total and phosphorylated tau protein using a cellular model of tauopathy. The redn. of tau was considered to be due to Rho-assocd. coiled-coil protein kinase (ROCK) inhibition by pitavastatin. ROCK plays important roles to organize the actin cytoskeleton, an expected therapeutic target of human disorders. Several ROCK inhibitors are clin. applied to prevent vasospasm postsubarachnoid hemorrhage (fasudil) and for the treatment of glaucoma (ripasudil). We have examd. the effects of ROCK inhibitors (H1152, Y-27632, and fasudil [HA-1077]) on tau protein phosphorylation in detail. A human neuroblastoma cell line (M1C cells) that expresses wild-type tau protein (4R0N) by tetracycline-off (TetOff) induction, primary cultured mouse neurons, and a mouse model of tauopathy (rTG4510 line) were used. The levels of phosphorylated tau and caspase-cleaved tau were reduced by the ROCK inhibitors. Oligomeric tau levels were also reduced by ROCK inhibitors. After ROCK inhibitor treatment, glycogen synthase kinase 3β, cyclin-dependent kinase 5, and caspase were inactivated, protein phosphatase 2A was activated, and the levels of IFN-γ were reduced. ROCK inhibitors activated autophagy and proteasome pathways, which are considered important for the degrdn. of tau protein. Collectively, these results suggest that ROCK inhibitors represent a viable therapeutic route to reduce the pathogenic forms of tau protein in tauopathies, including Alzheimer's disease.
- 64McKerracher, L.; Shenkar, R.; Abbinanti, M.; Cao, Y.; Peiper, A.; Liao, J. K.; Lightle, R.; Moore, T.; Hobson, N.; Gallione, C.; Ruschel, J.; Koskimäki, J.; Girard, R.; Rosen, K.; Marchuk, D. A.; Awad, I. A. A brain-targeted orally available ROCK2 inhibitor benefits mild and aggressive cavernous angioma disease. Transl. Stroke Res. 2020, 11, 365– 376, DOI: 10.1007/s12975-019-00725-8[Crossref], [PubMed], [CAS], Google Scholar64https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1ektr7L&md5=a34ed2f97907a6a3ef12f13d98f639a4A Brain-Targeted Orally Available ROCK2 Inhibitor Benefits Mild and Aggressive Cavernous Angioma DiseaseMcKerracher, Lisa; Shenkar, Robert; Abbinanti, Matthew; Cao, Ying; Peiper, Amy; Liao, James K.; Lightle, Rhonda; Moore, Thomas; Hobson, Nicholas; Gallione, Carol; Ruschel, Joerg; Koskimaki, Janne; Girard, Romuald; Rosen, Kenneth; Marchuk, Douglas A.; Awad, Issam A.Translational Stroke Research (2020), 11 (3), 365-376CODEN: TSRRDY; ISSN:1868-601X. (Springer)We investigated a novel ROCK2 selective inhibitor for ability to reduce brain lesion formation, growth, and maturation. We used genetic methods to explore the use of a ROCK2-selective kinase inhibitor to reduce growth and hemorrhage of CAs. The role of ROCK2 in CA was investigated by crossing Rock1 or Rock2 hemizygous mice with Ccm1 or Ccm3 hemizygous mice, and we found reduced lesions in the Rock2 hemizygous mice. A ROCK2-selective inhibitor, BA-1049 was used to investigate efficacy in reducing CA lesions after oral administration to Ccm1+/- and Ccm3+/- mice that were bred into a mutator background. After assessing the dose range effective to target brain endothelial cells in an ischemic brain model, Ccm1+/- and Ccm3+/- transgenic mice were treated for 3 (Ccm3+/-) or 4 mo (Ccm1+/-), concurrently, randomized to receive one of three doses of BA-1049 in drinking water, or placebo. Lesion vols. were assessed by micro-computed tomog. BA-1049 reduced activation of ROCK2 in Ccm3+/-Trp53-/- lesions. Mice treated with BA-1049 or placebo showed a significant dose-dependent redn. in lesion vol. after treatment with BA-1049, and a redn. in hemorrhage (iron deposition) near lesions at all doses. These translational studies show that BA-1049 is a promising therapeutic agent for the treatment of CA, a disease with no current treatment except surgical removal of the brain lesions.
- 65Zhao, L.; Li, Y.; Wang, Y.; Qiao, Z.; Miao, Z.; Yang, J.; Huang, L.; Tian, C.; Li, L.; Chen, D.; Yang, S. Discovery of 4H-chromen-4-one derivatives as a new class of selective rho kinase (ROCK) inhibitors, which showed potent activity in ex vivo diabetic retinopathy models. J. Med. Chem. 2019, 62, 10691– 10710, DOI: 10.1021/acs.jmedchem.9b01143[ACS Full Text], [CAS], Google Scholar65https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitFWgsL7K&md5=ed46c7ef57f79b8d77fded5ebe52ce6fDiscovery of 4H-Chromen-4-one Derivatives as a New Class of Selective Rho Kinase (ROCK) Inhibitors, which Showed Potent Activity in ex Vivo Diabetic Retinopathy ModelsZhao, Lanying; Li, Yueshan; Wang, Yujiao; Qiao, Zeen; Miao, Zhuang; Yang, Jiao; Huang, Luyi; Tian, Chenyu; Li, Linli; Chen, Danian; Yang, ShengyongJournal of Medicinal Chemistry (2019), 62 (23), 10691-10710CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Diabetic retinopathy (DR) is a major cause of blindness, and there is a lack of effective treatment at present. Rho-assocd. coiled-coil contg. serine/threonine protein kinases (ROCKs) have recently been suggested as potential targets for the DR treatment. We herein report the discovery of 4H-chromen-4-one derivs. as a new class of ROCK inhibitors. Structure-activity relationship analyses led to the identification of the most active compd., 4-(dimethylamino)-N-(3-{2-[(4-oxo-4H-chromen-7-yl)oxy]acetamido}phenyl) (12j). This compd. showed excellent kinase selectivity for ROCK I and ROCK II against 387 other kinases. In retinal explants, compd. 12j protected retinal neurons from high glucose-induced oxidative stress and apoptosis-mediated cell death. Furthermore, 12j administration suppressed the improper proliferation of M.ovrddot.uller cells and promoted the regression of vascular vessels in retinal explants cultured in a high glucose microenvironment. Collectively, our data suggest that 12j could be a potential lead compd. for the treatment of DR, hence deserving further in-depth studies.
- 66Mocsai, A.; Ruland, J.; Tybulewicz, V. L. The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat. Rev. Immunol. 2010, 10, 387– 402, DOI: 10.1038/nri2765[Crossref], [PubMed], [CAS], Google Scholar66https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXlvFOkurk%253D&md5=85857a2b9beb84e0fe74263a90fa8a53The SYK tyrosine kinase: a crucial player in diverse biological functionsMocsai, Attila; Ruland, Jurgen; Tybulewicz, Victor L. J.Nature Reviews Immunology (2010), 10 (6), 387-402CODEN: NRIABX; ISSN:1474-1733. (Nature Publishing Group)A review. Spleen tyrosine kinase (SYK) is known to have a crucial role in adaptive immune receptor signalling. However, recent reports indicate that SYK also mediates other, unexpectedly diverse biol. functions, including cellular adhesion, innate immune recognition, osteoclast maturation, platelet activation and vascular development. SYK is activated by C-type lectins and integrins, and activates new targets, including the CARD9-BCL-10-MALT1 pathway and the NLRP3 inflammasome. Studies using Drosophila melanogaster suggest that there is an evolutionarily ancient origin of SYK-mediated signalling. Moreover, SYK has a crucial role in autoimmune diseases and haematol. malignancies. This Review summarizes our current understanding of the diverse functions of SYK and how this is being translated for therapeutic purposes.
- 67Braselmann, S.; Taylor, V.; Zhao, H.; Wang, S.; Sylvain, C.; Baluom, M.; Qu, K.; Herlaar, E.; Lau, A.; Young, C.; Wong, B. R.; Lovell, S.; Sun, T.; Park, G.; Argade, A.; Jurcevic, S.; Pine, P.; Singh, R.; Grossbard, E. B.; Payan, D. G.; Masuda, E. S. R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation. J. Pharmacol. Exp. Ther. 2006, 319, 998– 1008, DOI: 10.1124/jpet.106.109058[Crossref], [PubMed], [CAS], Google Scholar67https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xht1yltL7P&md5=18fea516041ea075d2123158f321a186R406, an orally available spleen tyrosine kinase inhibitor blocks Fc receptor signaling and reduces immune complex-mediated inflammationBraselmann, Sylvia; Taylor, Vanessa; Zhao, Haoran; Wang, Su; Sylvain, Catherine; Baluom, Muhammad; Qu, Kunbin; Herlaar, Ellen; Lau, Angela; Young, Chi; Wong, Brian R.; Lovell, Scott; Sun, Thomas; Park, Gary; Argade, Ankush; Jurcevic, Stipo; Pine, Polly; Singh, Rajinder; Grossbard, Elliott B.; Payan, Donald G.; Masuda, Esteban S.Journal of Pharmacology and Experimental Therapeutics (2006), 319 (3), 998-1008CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)Recent compelling evidence has lead to renewed interest in the role of antibodies and immune complexes in the pathogenesis of several autoimmune disorders, such as rheumatoid arthritis. These immune complexes, consisting of autoantibodies to self-antigens, can mediate inflammatory responses largely through binding and activating the Ig Fc receptors (FcRs). Using cell-based structure activity relationships with cultured human mast cells, we have identified the small mol. R406 [N4-(2,2-dimethyl-3-oxo-4H-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2- (3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine] as a potent inhibitor of IgE (IgE)- and IgG-mediated activation of Fc receptor signaling (EC50 for degranulation = 56-64 nM). Here we show that the primary target for R406 is the spleen tyrosine kinase (Syk), which plays a key role in the signaling of activating Fc receptors and the B-cell receptor (BCR). R406 inhibited phosphorylation of Syk substrate linker for activation of T cells in mast cells and B-cell linker protein/SLP65 in B cells. R406 bound to the ATP binding pocket of Syk and inhibited its kinase activity as an ATP-competitive inhibitor (Ki = 30 nM). Furthermore, R406 blocked Syk-dependent FcR-mediated activation of monocytes/macrophages and neutrophils and BCR-mediated activation of B lymphocytes. R406 was selective as assessed using a large panel of Syk-independent cell-based assays representing both specific and general signaling pathways. Consistent with Syk inhibition, oral administration of R406 to mice reduced immune complex-mediated inflammation in a reverse-passive Arthus reaction and two antibody-induced arthritis models. Finally, we report a first-in-human study showing that R406 is orally bioavailable, achieving exposures capable of inhibiting Syk-dependent IgE-mediated basophil activation. Collectively, the results show R406 potential for modulating Syk activity in human disease.
- 68Markham, A. Fostamatinib: first global approval. Drugs 2018, 78, 959– 963, DOI: 10.1007/s40265-018-0927-1[Crossref], [PubMed], [CAS], Google Scholar68https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVOlsb7M&md5=e58fd226c946b7e2087a74d31eeba972Fostamatinib: First Global ApprovalMarkham, AnthonyDrugs (2018), 78 (9), 959-963CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)A review. Rigel Pharmaceuticals are developing the spleen tyrosine kinase (SYK) inhibitor fostamatinib (TAVALISSE) as a treatment for immune thrombocytopenia (ITP), autoimmune haemolytic anemia and IgA nephropathy. Based on pos. results in the phase III FIT clin. trial program, the drug was recently approved in the US as a treatment for thrombocytopenia in adult patients with chronic ITP who have had an insufficient response to a previous treatment. This article summarizes the milestones in the development of fostamatinib leading to this first approval.
- 69Alimova, M.; Sidhom, E.-H.; Satyam, A.; Dvela-Levitt, M.; Melanson, M.; Chamberlain, B. T.; Alper, S. L.; Santos, J.; Gutierrez, J.; Subramanian, A.; Grinkevich, E.; Bricio, E. R.; Kim, C.; Clark, A.; Watts, A.; Thompson, R.; Marshall, J.; Pablo, J. L.; Coraor, J.; Roignot, J.; Vernon, K. A.; Keller, K.; Campbell, A.; Emani, M.; Racette, M.; Bazua-Valenti, S.; Padovano, V.; Weins, A.; McAdoo, S. P.; Tam, F. W. K.; Ronco, L.; Wagner, F.; Tsokos, G. C.; Shaw, J. L.; Greka, A. A high content screen for mucin-1-reducing compounds identifies fostamatinib as a candidate for rapid repurposing for acute lung injury during the COVID-19 pandemic. bioRxiv 2020, DOI: 10.1101/2020.1106.1130.180380 .
- 70Liu, D.; Mamorska-Dyga, A. Syk inhibitors in clinical development for hematological malignancies. J. Hematol. Oncol. 2017, 10, 145, DOI: 10.1186/s13045-017-0512-1[Crossref], [PubMed], [CAS], Google Scholar70https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitV2gsrbJ&md5=ed423c793913414c2966af15bd4457c4Syk inhibitors in clinical development for hematological malignanciesLiu, Delong; Mamorska-Dyga, AleksandraJournal of Hematology & Oncology (2017), 10 (), 145/1-145/7CODEN: JHOOAO; ISSN:1756-8722. (BioMed Central Ltd.)Spleen tyrosine kinase (Syk) is a cytosolic non-receptor protein tyrosine kinase (PTK) and is mainly expressed in hematopoietic cells. Syk was recognized as a crit. element in the B-cell receptor signaling pathway. Syk is also a key component in signal transduction from other immune receptors like Fc receptors and adhesion receptors. Several oral Syk inhibitors including fostamatinib (R788), entospletinib (GS-9973), cerdulatinib (PRT062070), and TAK-659 are being assessed in clin. trials. The second generation compd., entospletinib, showed promising results in clin. trials against B-cell malignancies, mainly chronic lymphoid leukemia. Syk inhibitors are being evaluated in combination regimens in multiple malignancies.
- 71Norman, P. Spleen tyrosine kinase inhibitors: a review of the patent literature 2010 - 2013. Expert Opin. Ther. Pat. 2014, 24, 573– 595, DOI: 10.1517/13543776.2014.890184[Crossref], [PubMed], [CAS], Google Scholar71https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXmt1Ghu7o%253D&md5=6db9860a438ced1374f5b8727e3cd420Spleen tyrosine kinase inhibitors: a review of the patent literature 2010 - 2013Norman, PeterExpert Opinion on Therapeutic Patents (2014), 24 (5), 573-595CODEN: EOTPEG; ISSN:1354-3776. (Informa Healthcare)A review. Introduction: The non-receptor tyrosine kinase, spleen tyrosine kinase (Syk), is primarily expressed in hematopoietic cells and appears to be particularly important in B cells. Syk is involved in signal transduction processes and appears to regulate allergic, inflammatory and autoimmune responses. It also appears to play a significant role in the development of haematol. malignancies. Inhibitors of Syk are potentially useful in treating asthma, rheumatoid arthritis, lupus, chronic lymphocytic leukemia and lymphomas. Areas covered: This article reviews the increasing no. of patent filings between 2010 and 2013 claiming Syk inhibitors and focuses on the multiple structural classes of Syk inhibitors disclosed. It also comments on recent developments with Syk inhibitors, both clin. results and licensing deals. Expert opinion: The increased interest in the identification of Syk inhibitors has seen a sharp increase in patent filings claiming such compds. However, the no. of these is well below that of filings relating to other pro-inflammatory kinases (p38, JAK). These filings have also claimed an increasingly diverse range of chem. classes moving away from the 2,4-diaminopyrimidine motif present in drugs such as fostamatinib and PRT-06207. Many of the claimed compds. are Syk inhibitors with potencies considerably better than fostamatinib. However, good kinase selectivity is also likely to be essential if a Syk inhibitor is to prove useful enough to emulate the JAK inhibitor tofacitinib in gaining marketing authorization. Recent clin. failures with Syk inhibitors are expected to result in a decrease in the rate of patent filings claiming Syk inhibitors.
- 72Sharman, J.; Di Paolo, J. Targeting B-cell receptor signaling kinases in chronic lymphocytic leukemia: the promise of entospletinib. Ther. Adv. Hematol. 2016, 7, 157– 170, DOI: 10.1177/2040620716636542[Crossref], [PubMed], [CAS], Google Scholar72https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmvVWhtbc%253D&md5=6ad9438ca036afcf88753c128075d58cTargeting B-cell receptor signaling kinases in chronic lymphocytic leukemia: the promise of entospletinibSharman, Jeff; Di Paolo, JulieTherapeutic Advances in Hematology (2016), 7 (3), 157-170CODEN: TAHHAT; ISSN:2040-6207. (Sage Publications Ltd.)The B-cell receptor signaling pathway has emerged as an important therapeutic target in chronic lymphocytic leukemia and other B-cell malignancies. Novel agents have been developed targeting the signaling enzymes spleen tyrosine kinase (SYK), Bruton's tyrosine kinase, and phosphoinositide 3-kinase delta. This review discusses the rationale for targeting these enzymes, as well as the preclin. and clin. evidence supporting their role as therapeutic targets, with a particular focus on SYK inhibition with entospletinib.
- 73Blomgren, P.; Chandrasekhar, J.; Di Paolo, J. A.; Fung, W.; Geng, G.; Ip, C.; Jones, R.; Kropf, J. E.; Lansdon, E. B.; Lee, S.; Lo, J. R.; Mitchell, S. A.; Murray, B.; Pohlmeyer, C.; Schmitt, A.; Suekawa-Pirrone, K.; Wise, S.; Xiong, J. M.; Xu, J.; Yu, H.; Zhao, Z.; Currie, K. S. Discovery of lanraplenib (GS-9876): a once-daily Spleen tyrosine kinase inhibitor for autoimmune diseases. ACS Med. Chem. Lett. 2020, 11, 506– 513, DOI: 10.1021/acsmedchemlett.9b00621[ACS Full Text], [CAS], Google Scholar73https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXivVarsr4%253D&md5=6cf006a37622fa12e284721fbbb7f76cDiscovery of Lanraplenib (GS-9876): A Once-Daily Spleen Tyrosine Kinase Inhibitor for Autoimmune DiseasesBlomgren, Peter; Chandrasekhar, Jayaraman; Di Paolo, Julie A.; Fung, Wanchi; Geng, Guoju; Ip, Carmen; Jones, Randall; Kropf, Jeffrey E.; Lansdon, Eric B.; Lee, Seung; Lo, Jennifer R.; Mitchell, Scott A.; Murray, Bernard; Pohlmeyer, Chris; Schmitt, Aaron; Suekawa-Pirrone, Kimberly; Wise, Sarah; Xiong, Jin-Ming; Xu, Jianjun; Yu, Helen; Zhao, Zhongdong; Currie, Kevin S.ACS Medicinal Chemistry Letters (2020), 11 (4), 506-513CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Spleen tyrosine kinase (SYK) is a crit. regulator of signaling in a variety of immune cell types such as B-cells, monocytes, and macrophages. Accordingly, there have been numerous efforts to identify compds. that selectively inhibit SYK as a means to treat autoimmune and inflammatory diseases. We previously disclosed GS-9973 (entospletinib) as a selective SYK inhibitor that is under clin. evaluation in hematol. malignancies. However, a BID dosing regimen and drug interaction with proton pump inhibitors (PPI) prevented development of entospletinib in inflammatory diseases. Herein, we report the discovery of a second-generation SYK inhibitor, GS-9876 (lanraplenib), which has human pharmacokinetic properties suitable for once-daily administration and is devoid of any interactions with PPI. Lanraplenib is currently under clin. evaluation in multiple autoimmune indications.
- 74Pavel, A. B.; Song, T.; Kim, H. J.; Del Duca, E.; Krueger, J. G.; Dubin, C.; Peng, X.; Xu, H.; Zhang, N.; Estrada, Y. D.; Denis, L.; Rao, N.; Gupta, S.; Zammit, D. J.; Bissonnette, R.; Guttman-Yassky, E. Oral Janus kinase/SYK inhibition (ASN002) suppresses inflammation and improves epidermal barrier markers in patients with atopic dermatitis. J. Allergy Clin. Immunol. 2019, 144, 1011– 1024, DOI: 10.1016/j.jaci.2019.07.013[Crossref], [PubMed], [CAS], Google Scholar74https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1Cnt7bE&md5=004e714116fde700c464fca189d22fb6Oral Janus kinase/SYK inhibition (ASN002) suppresses inflammation and improves epidermal barrier markers in patients with atopic dermatitisPavel, Ana B.; Song, Teresa; Kim, Hyun-Je; Del Duca, Ester; Krueger, James G.; Dubin, Celina; Peng, Xiangyu; Xu, Hui; Zhang, Ning; Estrada, Yeriel D.; Denis, Louis; Rao, Niranjan; Gupta, Sandeep; Zammit, David J.; Bissonnette, Robert; Guttman-Yassky, EmmaJournal of Allergy and Clinical Immunology (2019), 144 (4), 1011-1024CODEN: JACIBY; ISSN:0091-6749. (Elsevier)We sought to evaluate the effect of ASN002 on the cellular and mol. biomarker profile of patients with moderate-to-severe AD and to correlate changes in biomarkers to improvements in clin. severity measures and pruritus. Thirty-six patients with moderate-to-severe AD were randomized to groups with dose escalation of ASN002 (20, 40, and 80 mg) and a placebo group. Skin biopsy specimens were performed at baseline, day 15, and day 29. It also rapidly and significantly suppressed key inflammatory pathways implicated in AD pathogenesis, including TH2 (IL4 receptor [IL4R], IL13, CCL13/monocyte chemoattractant protein 4, CCL17/thymus and activation-regulated chemokine, CCL18/pulmonary and activation-regulated chemokine, CCL22/macrophage-derived chemokine, and CCL26/eotaxin-3), TH17/TH22 (lipocalins, PI3/elafin, CCL20, S100A7/S100A8/S100A9, and IL36G/IL36RN), and TH1 (IFNG, CXCL9/CXCL11, and MX1) axes and barrier-related measures (filaggrin [FLG] and CLDN23). Significant improvements in AD gene signatures were obsd. predominantly in the 40- and 80-mg groups. Smaller and largely nonsignificant mol. changes were seen in the 20-mg and placebo groups. The Janus kinase/spleen tyrosine kinase inhibitor ASN002 significantly suppressed key AD inflammatory pathways, corresponding to clin. response. ASN002 might be an effective novel therapeutic agent for moderate-to-severe AD.
- 75Barker, M. D.; Liddle, J.; Atkinson, F. L.; Wilson, D. M.; Dickson, M. C.; Ramirez-Molina, C.; Lewis, H.; Davis, R. P.; Somers, D. O.; Neu, M.; Jones, E.; Watson, R. Discovery of potent and selective Spleen Tyrosine Kinase inhibitors for the topical treatment of inflammatory skin disease. Bioorg. Med. Chem. Lett. 2018, 28, 3458– 3462, DOI: 10.1016/j.bmcl.2018.09.022[Crossref], [PubMed], [CAS], Google Scholar75https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslOksLzI&md5=508d42b03e2fedad09221f01a6762026Discovery of potent and selective Spleen Tyrosine Kinase inhibitors for the topical treatment of inflammatory skin diseaseBarker, Michael D.; Liddle, John; Atkinson, Francis L.; Wilson, David Matthew; Dickson, Marion C.; Ramirez-Molina, Cesar; Lewis, Huw; Davis, Rob P.; Somers, Donald O.; Neu, Margarete; Jones, Emma; Watson, RobertBioorganic & Medicinal Chemistry Letters (2018), 28 (21), 3458-3462CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)The discovery and lead optimization of a novel series of SYK inhibitors is described. These were optimized for SYK potency and selectivity against Aurora B. Compds. were profiled in a human skin penetration study to identify a suitable candidate mol. for pre-clin. development. Compd. 44 (GSK2646264) was selected for progression and is currently in Phase I clin. trials.
- 76Paris, D.; Ait-Ghezala, G.; Bachmeier, C.; Laco, G.; Beaulieu-Abdelahad, D.; Lin, Y.; Jin, C.; Crawford, F.; Mullan, M. The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation. J. Biol. Chem. 2014, 289, 33927– 33944, DOI: 10.1074/jbc.M114.608091[Crossref], [PubMed], [CAS], Google Scholar76https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVClurfL&md5=66b700e3cb27a1037c16ad9681d1b35aThe Spleen Tyrosine Kinase (Syk) Regulates Alzheimer Amyloid-β Production and Tau HyperphosphorylationParis, Daniel; Ait-Ghezala, Ghania; Bachmeier, Corbin; Laco, Gary; Beaulieu-Abdelahad, David; Lin, Yong; Jin, Chao; Crawford, Fiona; Mullan, MichaelJournal of Biological Chemistry (2014), 289 (49), 33927-33944CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)We have previously shown that the L-type calcium channel (LCC) antagonist nilvadipine reduces brain amyloid-β (Aβ) accumulation by affecting both Aβ prodn. and Aβ clearance across the blood-brain barrier (BBB). Nilvadipine consists of a mixt. of two enantiomers, (+)-nilvadipine and (-)-nilvadipine, in equal proportion. (+)-Nilvadipine is the active enantiomer responsible for the inhibition of LCC, whereas (-)-nilvadipine is considered inactive. Both nilvadipine enantiomers inhibit Aβ prodn. and improve the clearance of Aβ across the BBB showing that these effects are not related to LCC inhibition. In addn., treatment of P301S mutant human Tau transgenic mice (transgenic Tau P301S) with (-)-nilvadipine reduces Tau hyperphosphorylation at several Alzheimer disease (AD) pertinent epitopes. A search for the mechanism of action of (-)-nilvadipine revealed that this compd. inhibits the spleen tyrosine kinase (Syk). We further validated Syk as a target-regulating Aβ by showing that pharmacol. inhibition of Syk or down-regulation of Syk expression reduces Aβ prodn. and increases the clearance of Aβ across the BBB mimicking (-)-nilvadipine effects. Moreover, treatment of transgenic mice overexpressing Aβ and transgenic Tau P301S mice with a selective Syk inhibitor resp. decreased brain Aβ accumulation and Tau hyperphosphorylation at multiple AD relevant epitopes. We show that Syk inhibition induces an increased phosphorylation of the inhibitory Ser-9 residue of glycogen synthase kinase-3β, a primary Tau kinase involved in Tau phosphorylation, by activating protein kinase A, providing a mechanism explaining the redn. of Tau phosphorylation at GSK3β-dependent epitopes following Syk inhibition. Altogether our data highlight Syk as a promising target for preventing both Aβ accumulation and Tau hyperphosphorylation in AD.
- 77Bryan, M. C.; Rajapaksa, N. S. Kinase inhibitors for the treatment of immunological disorders: recent advances. J. Med. Chem. 2018, 61, 9030– 9058, DOI: 10.1021/acs.jmedchem.8b00667[ACS Full Text], [CAS], Google Scholar77https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVOmsLzI&md5=aff62adff54c9152d2b2156b05d67400Kinase Inhibitors for the Treatment of Immunological Disorders: Recent AdvancesBryan, Marian C.; Rajapaksa, Naomi S.Journal of Medicinal Chemistry (2018), 61 (20), 9030-9058CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Small mol. inhibitors targeting autoimmune and inflammatory processes have been an area of intense focus within academia and industry. Much of this work has been aimed at key kinases operating as central nodes in inflammatory signaling pathways. While this focus has led to over 30 FDA-approved small mol. kinase inhibitors, only one is currently approved for autoimmune and inflammatory diseases. Despite this lack of success, there remains tremendous reason for excitement. Our growing understanding of the biol. involved in the inflammatory response, the factors that lead to safer small mol. kinase inhibitors, and the availability of selective tool mols. for interrogating specific nodes and pathways are all pushing the field forward. This article focuses on recent developments requiring novel approaches to create safe and effective small mol. kinase inhibitors and where further work is needed to realize the promise of small mol. kinase inhibitors for patient benefit.
- 78Saxton, R. A.; Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 2017, 169, 361– 371, DOI: 10.1016/j.cell.2017.03.035[Crossref], [PubMed], [CAS], Google Scholar78https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXlvVKhsr8%253D&md5=5e3235c6302939ada00fc0e8d3f04293mTOR Signaling in Growth, Metabolism, and Disease [Erratum to document cited in CA166:281944]Saxton, Robert A.; Sabatini, David M.Cell (Cambridge, MA, United States) (2017), 169 (2), 361-371CODEN: CELLB5; ISSN:0092-8674. (Cell Press)Earlier drafts of the figures in this Review were published in print and online; the figures have been updated online. The information that the earlier figures contained was accurate and complete.
- 79Xu, K.; Liu, P.; Wei, W. mTOR signaling in tumorigenesis. Biochim. Biophys. Acta, Rev. Cancer 2014, 1846, 638– 654, DOI: 10.1016/j.bbcan.2014.10.007[Crossref], [PubMed], [CAS], Google Scholar79https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvV2msLjI&md5=18af080856fbb55a7f717689555c25fdmTOR signaling in tumorigenesisXu, Kai; Liu, Pengda; Wei, WenyiBiochimica et Biophysica Acta, Reviews on Cancer (2014), 1846 (2), 638-654CODEN: BBACEU; ISSN:0304-419X. (Elsevier B.V.)A review. MTOR (the mechanistic target of rapamycin) is an atypical serine/threonine kinase involved in regulating major cellular functions including growth and proliferation. Deregulation of the mTOR signaling pathway is one of the most commonly obsd. pathol. alterations in human cancers. To this end, oncogenic activation of the mTOR signaling pathway contributes to cancer cell growth, proliferation and survival, highlighting the potential for targeting the oncogenic mTOR pathway members as an effective anti-cancer strategy. In order to do so, a thorough understanding of the physiol. roles of key mTOR signaling pathway components and upstream regulators would guide future targeted therapies. Thus, in this review, we summarize available genetic mouse models for mTORC1 and mTORC2 components, as well as characterized mTOR upstream regulators and downstream targets, and assign a potential oncogenic or tumor suppressive role for each evaluated mol. Together, our work will not only facilitate the current understanding of mTOR biol. and possible future research directions, but more importantly, provide a mol. basis for targeted therapies aiming at key oncogenic members along the mTOR signaling pathway.
- 80Abdel-Maksoud, M. S.; El-Gamal, M. I.; Benhalilou, D. R.; Ashraf, S.; Mohammed, S. A.; Oh, C. H. Mechanistic/mammalian target of rapamycin: Recent pathological aspects and inhibitors. Med. Res. Rev. 2019, 39, 631– 664, DOI: 10.1002/med.21535[Crossref], [PubMed], [CAS], Google Scholar80https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3czisVSmug%253D%253D&md5=bacb5a2917bf3efa439587b6a54c2dc1Mechanistic/mammalian target of rapamycin: Recent pathological aspects and inhibitorsAbdel-Maksoud Mohammed S; El-Gamal Mohammed I; Benhalilou Dalia Reyane; Ashraf Sandy; Mohammed Shatha Abdulghaffar; El-Gamal Mohammed I; Oh Chang-Hyun; Oh Chang-HyunMedicinal research reviews (2019), 39 (2), 631-664 ISSN:.The mechanistic/mammalian target of rapamycin (mTOR), also known as the mechanistic target of rapamycin, regulates many normal cell processes such as transcription, cell growth, and autophagy. Overstimulation of mTOR by its ligands, amino acids, sugars, and/or growth factors leads to physiological disorders, including cancer and neurodegenerative diseases. In this study, we reviewed the recent advances regarding the mechanism that involves mTOR in cancer, aging, and neurodegenerative diseases. The chemical and biological properties of recently reported small molecules that function as mTOR kinase inhibitors, including adenosine triphosphate-competitive inhibitors and dual mTOR/PI3K inhibitors, have also been reviewed. We focused on the reports published in the literature from 2012 to 2017.
- 81Populo, H.; Lopes, J. M.; Soares, P. The mTOR signalling pathway in human cancer. Int. J. Mol. Sci. 2012, 13, 1886– 1918, DOI: 10.3390/ijms13021886[Crossref], [PubMed], [CAS], Google Scholar81https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XivVKhtro%253D&md5=e6c6c9f80fe1a40d4431bd9dfe0d1e45The mTOR signalling pathway in human cancerPopulo, Helena; Lopes, Jose Manuel; Soares, PaulaInternational Journal of Molecular Sciences (2012), 13 (), 1886-1918CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)A review. The conserved serine/threonine kinase mTOR (the mammalian target of rapamycin), a downstream effector of the PI3K/AKT pathway, forms two distinct multiprotein complexes: mTORC1 and mTORC2. MTORC1 is sensitive to rapamycin, activates S6K1 and 4EBP1, which are involved in mRNA translation. It is activated by diverse stimuli, such as growth factors, nutrients, energy and stress signals, and essential signalling pathways, such as PI3K, MAPK and AMPK, in order to control cell growth, proliferation and survival. MTORC2 is considered resistant to rapamycin and is generally insensitive to nutrients and energy signals. It activates PKC-α and AKT and regulates the actin cytoskeleton. Deregulation of multiple elements of the mTOR pathway (PI3K amplification/mutation, PTEN loss of function, AKT overexpression, and S6K1, 4EBP1 and eIF4E overexpression) has been reported in many types of cancers, particularly in melanoma, where alterations in major components of the mTOR pathway were reported to have significant effects on tumor progression. Therefore, mTOR is an appealing therapeutic target and mTOR inhibitors, including the rapamycin analogs deforolimus, everolimus and temsirolimus, are submitted to clin. trials for treating multiple cancers, alone or in combination with inhibitors of other pathways. Importantly, temsirolimus and everolimus were recently approved by the FDA for the treatment of renal cell carcinoma, PNET and giant cell astrocytoma. Small mols. that inhibit mTOR kinase activity and dual PI3K-mTOR inhibitors are also being developed. In this review, we aim to survey relevant research, the mol. mechanisms of signalling, including upstream activation and downstream effectors, and the role of mTOR in cancer, mainly in melanoma.
- 82Easton, J. B.; Houghton, P. J. mTOR and cancer therapy. Oncogene 2006, 25, 6436– 6446, DOI: 10.1038/sj.onc.1209886[Crossref], [PubMed], [CAS], Google Scholar82https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtVOlsrrN&md5=7a676e4128d249409e320924b26356ebmTOR and cancer therapyEaston, J. B.; Houghton, P. J.Oncogene (2006), 25 (48), 6436-6446CODEN: ONCNES; ISSN:0950-9232. (Nature Publishing Group)A review. Proteins regulating the mammalian target of rapamycin (mTOR), as well as some of the targets of the mTOR kinase, are overexpressed or mutated in cancer. Rapamycin, the naturally occurring inhibitor of mTOR, along with a no. of recently developed rapamycin analogs (rapalogs) consisting of synthetically derived compds. contg. minor chem. modifications to the parent structure, inhibit the growth of cell lines derived from multiple tumor types in vitro, and tumor models in vivo. Results from clin. trials indicate that the rapalogs may be useful for the treatment of subsets of certain types of cancer. The sporadic responses from the initial clin. trials, based on the hypothesis of general translation inhibition of cancer cells are now beginning to be understood owing to a more complete understanding of the dynamics of mTOR regulation and the function of mTOR in the tumor microenvironment. This review will summarize the preclin. and clin. data and recent discoveries of the function of mTOR in cancer and growth regulation.
- 83Mandrioli, J.; D’Amico, R.; Zucchi, E.; Gessani, A.; Fini, N.; Fasano, A.; Caponnetto, C.; Chio, A.; Dalla Bella, E.; Lunetta, C.; Mazzini, L.; Marinou, K.; Soraru, G.; de Biasi, S.; Lo Tartaro, D.; Pinti, M.; Cossarizza, A. Rapamycin treatment for amyotrophic lateral sclerosis: Protocol for a phase II randomized, double-blind, placebo-controlled, multicenter, clinical trial (RAP-ALS trial). Medicine (Philadelphia, PA, U. S.) 2018, 97, e11119 DOI: 10.1097/MD.0000000000011119[Crossref], [CAS], Google Scholar83https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFWrtbrK&md5=aa30fc88e15b0dc8ac2352b3bb993addRapamycin treatment for amyotrophic lateral sclerosis: Protocol for a phase II randomized, double-blind, placebo-controlled, multicenter, clinical trial (RAP-ALS trial)Mandrioli, Jessica; D'Amico, Roberto; Zucchi, Elisabetta; Gessani, Annalisa; Fini, Nicola; Fasano, Antonio; Caponnetto, Claudia; Chio, Adriano; Dalla Bella, Eleonora; Lunetta, Christian; Mazzini, Letizia; Marinou, Kalliopi; Soraru, Gianni; de Biasi, Sara; Lo Tartaro, Domenico; Pinti, Marcello; Cossarizza, AndreaMedicine (Philadelphia, PA, United States) (2018), 97 (24), e11119CODEN: MEDIAV; ISSN:0025-7974. (Lippincott Williams & Wilkins)Misfolded aggregated proteins and neuroinflammation significantly contribute to amyotrophic lateral sclerosis (ALS) pathogenesis, hence representing therapeutic targets to modify disease expression. Rapamycin inhibits mechanistic target of Rapamycin (mTOR) pathway and enhances autophagy with demonstrated beneficial effects in neurodegeneration in cell line and animal models, improving phenotype in SQSTM1 zebrafish, in Drosophila model of ALS-TDP, and in the TDP43 mouse model, in which it reduced neuronal loss and TDP43 inclusions. Rapamycin also expands regulatory T lymphocytes (Treg) and increased Treg levels are assocd. with slow progression in ALS patients.Therefore, we planned a randomized clin. trial testing Rapamycin treatment in ALS patients. RAP-ALS is a phase II randomized, double-blind, placebo-controlled, multicenter (8 ALS centers in Italy), clin. trial. The primary aim is to assess whether Rapamycin administration increases Tregs no. in treated patients compared with control arm. Secondary aims include the assessment of safety and tolerability of Rapamycin in patients with ALS; the min. dosage to have Rapamycin in cerebrospinal fluid; changes in immunol. (activation and homing of T, B, NK cell subpopulations) and inflammatory markers, and on mTOR downstream pathway (S6RP phosphorylation); clin. activity (ALS Functional Rating Scale-Revised, survival, forced vital capacity); and quality of life (ALSAQ40 scale). Rapamycin potentially targets mechanisms at play in ALS (i.e., autophagy and neuroinflammation), with promising preclin. studies. It is an already approved drug, with known pharmacokinetics, already available and therefore with significant possibility of rapid translation to daily clinics. Findings will provide reliable data for further potential trials. The study protocol was approved by the Ethics Committee of Azienda Ospedaliero Universitaria of Modena and by the Ethics Committees of participating centers (Eudract n. 2016-002399-28) based on the Helsinki declaration.
- 84Bonazzi, S.; Goold, C. P.; Gray, A.; Thomsen, N. M.; Nunez, J.; Karki, R. G.; Gorde, A.; Biag, J. D.; Malik, H. A.; Sun, Y.; Liang, G.; Lubicka, D.; Salas, S.; Labbe-Giguere, N.; Keaney, E. P.; McTighe, S.; Liu, S.; Deng, L.; Piizzi, G.; Lombardo, F.; Burdette, D.; Dodart, J. C.; Wilson, C. J.; Peukert, S.; Curtis, D.; Hamann, L. G.; Murphy, L. O. Discovery of a brain-penetrant ATP-competitive inhibitor of the mechanistic target of rapamycin (mTOR) for CNS disorders. J. Med. Chem. 2020, 63, 1068– 1083, DOI: 10.1021/acs.jmedchem.9b01398[ACS Full Text], [CAS], Google Scholar84https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXht1CktLo%253D&md5=d52546d7050d5e45b4fd241506004ef1Discovery of a Brain-Penetrant ATP-Competitive Inhibitor of the Mechanistic Target of Rapamycin (mTOR) for CNS DisordersBonazzi, Simone; Goold, Carleton P.; Gray, Audrey; Thomsen, Noel M.; Nunez, Jill; Karki, Rajeshri G.; Gorde, Aakruti; Biag, Jonathan D.; Malik, Hasnain A.; Sun, Yingchuan; Liang, Guiqing; Lubicka, Danuta; Salas, Sarah; Labbe-Giguere, Nancy; Keaney, Erin P.; McTighe, Stephanie; Liu, Shanming; Deng, Lin; Piizzi, Grazia; Lombardo, Franco; Burdette, Doug; Dodart, Jean-Cosme; Wilson, Christopher J.; Peukert, Stefan; Curtis, Daniel; Hamann, Lawrence G.; Murphy, Leon O.Journal of Medicinal Chemistry (2020), 63 (3), 1068-1083CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Recent clin. evaluation of everolimus for seizure redn. in patients with tuberous sclerosis complex (TSC), a disease with overactivated mechanistic target of rapamycin (mTOR) signaling, has demonstrated the therapeutic value of mTOR inhibitors for central nervous system (CNS) indications. Given that everolimus is an incomplete inhibitor of the mTOR function, we sought to develop a new mTOR inhibitor that has improved properties and is suitable for CNS disorders. Starting from an inhouse purine-based compd., optimization of the physicochem. properties of a thiazolopyrimidine series led to the discovery of the small mol. 7, a potent and selective brain-penetrant ATP-competitive mTOR inhibitor. In neuronal cell-based models of mTOR hyperactivity, 7 cor. the mTOR pathway activity and the resulting neuronal overgrowth phenotype. The new mTOR inhibitor 7 showed good brain exposure and significantly improved the survival rate of mice with neuronal-specific ablation of the Tsc1 gene. These results demonstrate the potential utility of this tool compd. to test therapeutic hypotheses that depend on mTOR hyperactivity in the CNS.
- 85Cansfield, A. D.; Ladduwahetty, T.; Sunose, M.; Ellard, K.; Lynch, R.; Newton, A. L.; Lewis, A.; Bennett, G.; Zinn, N.; Thomson, D. W.; Ruger, A. J.; Feutrill, J. T.; Rausch, O.; Watt, A. P.; Bergamini, G. CZ415, a highly selective mTOR inhibitor showing in vivo efficacy in a collagen induced arthritis model. ACS Med. Chem. Lett. 2016, 7, 768– 773, DOI: 10.1021/acsmedchemlett.6b00149[ACS Full Text], [CAS], Google Scholar85https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XpsF2mtr4%253D&md5=75b75c43427a76438e110251abd052b4CZ415, a Highly Selective mTOR Inhibitor Showing in Vivo Efficacy in a Collagen Induced Arthritis ModelCansfield, Andrew D.; Ladduwahetty, Tammy; Sunose, Mihiro; Ellard, Katie; Lynch, Rosemary; Newton, Anthea L.; Lewis, Ann; Bennett, Gavin; Zinn, Nico; Thomson, Douglas W.; Ruger, Anne J.; Feutrill, John T.; Rausch, Oliver; Watt, Alan P.; Bergamini, GiovannaACS Medicinal Chemistry Letters (2016), 7 (8), 768-773CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)CZ415, a potent ATP-competitive mTOR inhibitor with unprecedented selectivity over any other kinase is described. In addn. to a comprehensive characterization of its activities in vitro, in vitro ADME, and in vivo pharmacokinetic data are reported. The suitability of this inhibitor for studying in vivo mTOR biol. is demonstrated in a mechanistic mouse model monitoring mTOR proximal downstream phosphorylation signaling. Furthermore, the compd. reported here is the first ATP-competitive mTOR inhibitor described to show efficacy in a semitherapeutic collagen induced arthritis (CIA) mouse model.
- 86Yang, M.; Huang, L.; Li, X.; Kuang, E. Chloroquine inhibits lytic replication of Kaposi’s sarcoma-associated herpesvirus by disrupting mTOR and p38-MAPK activation. Antiviral Res. 2016, 133, 223– 233, DOI: 10.1016/j.antiviral.2016.08.010[Crossref], [PubMed], [CAS], Google Scholar86https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVehur3J&md5=54b3de95bc36cf693afc5b6461ad7bedChloroquine inhibits lytic replication of Kaposi's sarcoma-associated herpesvirus by disrupting mTOR and p38-MAPK activationYang, Mengtian; Huang, Lu; Li, Xiaojuan; Kuang, ErshengAntiviral Research (2016), 133 (), 223-233CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)Lytic infection is essential for the persistent infection and pathogenesis of Kaposi's sarcoma-assocd. herpesvirus (KSHV), and inhibiting KSHV lytic replication may effectively prevent the occurrence of KSHV-related diseases. Chloroquine (CQ), a well-known antimalarial drug and autophagy inhibitor, exerts broad-spectrum antiviral effects and shows anti-cancer therapeutic potential. However, the ability of CQ and its derivs. to control infection of oncogenic γ-herpesvirus remains undefined. Here we reveal that CQ suppresses KSHV lytic gene expression and virion prodn., and shows cytotoxicity toward KSHV lytically infected B cells at clin. acceptable doses. CQ suppresses mTOR and p38-MAPK pathway activation during KSHV lytic replication but not latent infection. Furthermore, CQ blocks Epstein-Barr virus (EBV) lytic replication via a distinct mechanism that is invoked to block virion prodn. but does not affect viral gene expression. These results suggest that CQ is an effective antiviral drug against KSHV lytic infection. Our findings indicate that CQ treatment should be considered for controlling KSHV-related diseases, particularly for primary use in co-infection of KSHV with malaria.
- 87Liu, Q.; Chang, J. W.; Wang, J.; Kang, S. A.; Thoreen, C. C.; Markhard, A.; Hur, W.; Zhang, J.; Sim, T.; Sabatini, D. M.; Gray, N. S. Discovery of 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benz o[h][1,6]naphthyridin-2(1H)-one as a highly potent, selective mammalian target of rapamycin (mTOR) inhibitor for the treatment of cancer. J. Med. Chem. 2010, 53, 7146– 7155, DOI: 10.1021/jm101144f[ACS Full Text], [CAS], Google Scholar87https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtF2nu7nN&md5=596ca3d515dd124c11f314dc92f551b9Discovery of 1-(4-(4-Propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo[h][1,6]naphthyridin-2(1H)-one as a highly potent, selective mammalian target of rapamycin (mTOR) inhibitor for the treatment of cancerLiu, Qingsong; Chang, Jae Won; Wang, Jinhua; Kang, Seong A.; Thoreen, Carson C.; Markhard, Andrew; Hur, Wooyoung; Zhang, Jianming; Sim, Taebo; Sabatini, David M.; Gray, Nathanael S.Journal of Medicinal Chemistry (2010), 53 (19), 7146-7155CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The mTOR protein is a master regulator of cell growth and proliferation, and inhibitors of its kinase activity have the potential to become new class of anticancer drugs. Starting from quinoline I, which was identified in a biochem. mTOR assay, we developed a tricyclic benzonaphthyridinone inhibitor II (Torin1), which inhibited phosphorylation of mTORC1 and mTORC2 substrates in cells at concns. of 2 and 10 nM, resp. Moreover, Torin1 exhibits 1000-fold selectivity for mTOR over PI3K (EC50 = 1800 nM) and exhibits 100-fold binding selectivity relative to 450 other protein kinases. Torin1 was efficacious at a dose of 20 mg/kg in a U87MG xenograft model and demonstrated good pharmacodynamic inhibition of downstream effectors of mTOR in tumor and peripheral tissues. These results demonstrate that Torin1 is a useful probe of mTOR-dependent phenomena and that benzonaphthridinones represent a promising scaffold for the further development of mTOR-specific inhibitors with the potential for clin. utility.
- 88Choi, S.; Kim, K.; Cha, M.; Kim, M.; Lee, B. H. mTOR signaling intervention by Torin1 and XL388 in the insular cortex alleviates neuropathic pain. Neurosci. Lett. 2020, 718, 134742, DOI: 10.1016/j.neulet.2020.134742[Crossref], [PubMed], [CAS], Google Scholar88https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3MbotVOrsA%253D%253D&md5=b416e1cba9b916950dc703add029fcb2mTOR signaling intervention by Torin1 and XL388 in the insular cortex alleviates neuropathic painChoi Songyeon; Kim Kyeongmin; Cha Myeounghoon; Kim Minjee; Lee Bae HwanNeuroscience letters (2020), 718 (), 134742 ISSN:.Signaling by mammalian target of rapamycin (mTOR), a kinase regulator of protein synthesis, has been implicated in the development of chronic pain. The mTOR comprises two distinct protein complexes, mTOR complex 1 (mTORC1) and mTORC2. Although effective inhibitors of mTORC1 and C2 have been developed, studies on the effect of these inhibitors related to pain modulation are still lacking. This study was conducted to determine the inhibitory effects of Torin1 and XL388 in an animal model of neuropathic pain. Seven days after neuropathic surgery, Torin1 or XL388 were microinjected into the insular cortex (IC) of nerve-injured animals and behavioral changes were assessed. Administration of Torin1 or XL388 into the IC significantly increased mechanical thresholds and reduced mechanical allodynia. At the immunoblotting results, Torin1 and XL388 significantly reduced phosphorylation of mTOR, 4E-BP1, p70S6K, and PKCα, without affecting Akt. These results strongly suggest that Torin1 and XL388 may attenuate neuropathic pain via inhibition of mTORC1 and mTORC2 in the IC.
- 89Liu, Q.; Wang, J.; Kang, S. A.; Thoreen, C. C.; Hur, W.; Ahmed, T.; Sabatini, D. M.; Gray, N. S. Discovery of 9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2) as a potent, selective, and orally available mammalian target of rapamycin (mTOR) inhibitor for treatment of cancer. J. Med. Chem. 2011, 54, 1473– 1480, DOI: 10.1021/jm101520v[ACS Full Text], [CAS], Google Scholar89https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhvFeis7c%253D&md5=845ed4ca35e5544954db71cd6813528eDiscovery of 9-(6-Aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2) as a potent, selective, and orally available mammalian target of rapamycin (mTOR) inhibitor for treatment of cancerLiu, Qingsong; Wang, Jinhua; Kang, Seong A.; Thoreen, Carson C.; Hur, Wooyoung; Ahmed, Tausif; Sabatini, David M.; Gray, Nathanael S.Journal of Medicinal Chemistry (2011), 54 (5), 1473-1480CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The mTOR mediated PI3K/AKT/mTOR signal transduction pathway has been demonstrated to play a key role in a broad spectrum of cancers. Starting from the mTOR selective inhibitor 1 (Torin1), a focused medicinal chem. effort led to the discovery of an improved mTOR inhibitor 3 (Torin2, I), which possesses an EC50 of 0.25 nM for inhibiting cellular mTOR activity. Compd. 3 exhibited 800-fold selectivity over PI3K (EC50: 200 nM) and over 100-fold binding selectivity relative to 440 other protein kinases. Compd. 3 has significantly improved bioavailability (54%), metabolic stability, and plasma exposure relative to compd. 1.
- 90Hanson, K. K.; Ressurreicao, A. S.; Buchholz, K.; Prudencio, M.; Herman-Ornelas, J. D.; Rebelo, M.; Beatty, W. L.; Wirth, D. F.; Hanscheid, T.; Moreira, R.; Marti, M.; Mota, M. M. Torins are potent antimalarials that block replenishment of Plasmodium liver stage parasitophorous vacuole membrane proteins. Proc. Natl. Acad. Sci. U. S. A. 2013, 110, E2838– 2847, DOI: 10.1073/pnas.1306097110[Crossref], [PubMed], [CAS], Google Scholar90https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1elsr%252FF&md5=248aa67f94cc846c89b9bd4052244070Torins are potent antimalarials that block replenishment of Plasmodium liver stage parasitophorous vacuole membrane proteinsHanson, Kirsten K.; Ressurreicao, Ana S.; Buchholz, Kathrin; Prudencio, Miguel; Herman-Ornelas, Jonathan D.; Rebelo, Maria; Beatty, Wandy L.; Wirth, Dyann F.; Hanscheid, Thomas; Moreira, Rui; Marti, Matthias; Mota, Maria M.Proceedings of the National Academy of Sciences of the United States of America (2013), 110 (30), E2838-E2847,SE2838/1-SE2838/8CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Residence within a customized vacuole is a highly successful strategy used by diverse intracellular microorganisms. The parasitophorous vacuole membrane (PVM) is the crit. interface between Plasmodium parasites and their possibly hostile, yet ultimately sustaining, host cell environment. The authors show that torins, developed as ATP-competitive mammalian target of rapamycin (mTOR) kinase inhibitors, are fast-acting antiplasmodial compds. that unexpectedly target the parasite directly, blocking the dynamic trafficking of the Plasmodium proteins exported protein 1 (EXP1) and upregulated in sporozoites 4 (UIS4) to the liver stage PVM and leading to efficient parasite elimination by the hepatocyte. Torin2 has single-digit, or lower, nanomolar potency in both liver and blood stages of infection in vitro and is likewise effective against both stages in vivo, with a single oral dose sufficient to clear liver stage infection. Parasite elimination and perturbed trafficking of liver stage PVM-resident proteins are both specific aspects of torin-mediated Plasmodium liver stage inhibition, indicating that torins have a distinct mode of action compared with currently used antimalarials.
- 91Xue, Q.; Hopkins, B.; Perruzzi, C.; Udayakumar, D.; Sherris, D.; Benjamin, L. E. Palomid 529, a novel small-molecule drug, is a TORC1/TORC2 inhibitor that reduces tumor growth, tumor angiogenesis, and vascular permeability. Cancer Res. 2008, 68, 9551– 9557, DOI: 10.1158/0008-5472.CAN-08-2058[Crossref], [PubMed], [CAS], Google Scholar91https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtlOmt7nE&md5=5288bb78a6b4f2685fde809f08d8086aPalomid 529, a Novel Small-Molecule Drug, Is a TORC1/TORC2 Inhibitor That Reduces Tumor Growth, Tumor Angiogenesis, and Vascular PermeabilityXue, Qi; Hopkins, Benjamin; Perruzzi, Carole; Udayakumar, Durga; Sherris, David; Benjamin, Laura E.Cancer Research (2008), 68 (22), 9551-9557CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)It has become clear that the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is central for promoting both tumor and tumor stroma and is therefore a major target for anticancer drug development. First- and second-generation rapalogs (prototypical mTOR inhibitors) have shown promise but, due to the complex nature of mTOR signaling, can result in counterproductive feedback signaling to potentiate upstream Akt signaling. We present a novel PI3K/Akt/mTOR inhibitor, Palomid 529 (P529), which inhibits the TORC1 and TORC2 complexes and shows both inhibition of Akt signaling and mTOR signaling similarly in tumor and vasculature. We show that P529 inhibits tumor growth, angiogenesis, and vascular permeability. It retains the beneficial aspects of tumor vascular normalization that rapamycin boasts. However, P529 has the addnl. benefit of blocking pAktS473 signaling consistent with blocking TORC2 in all cells and thus bypassing feedback loops that lead to increased Akt signaling in some tumor cells.
- 92Dalal, M.; Jacobs-El, N.; Nicholson, B.; Tuo, J.; Chew, E.; Chan, C. C.; Nussenblatt, R.; Ferris, F.; Meyerle, C. Subconjunctival Palomid 529 in the treatment of neovascular age-related macular degeneration. Graefe's Arch. Clin. Exp. Ophthalmol. 2013, 251, 2705– 2709, DOI: 10.1007/s00417-013-2375-7[Crossref], [PubMed], [CAS], Google Scholar92https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFCit7nL&md5=a94310abffe147aaccacf41fcd5bef7fSubconjunctival Palomid 529 in the treatment of neovascular age-related macular degenerationDalal, Monica; Jacobs-El, Naima; Nicholson, Benjamin; Tuo, Jingsheng; Chew, Emily; Chan, Chi-Chao; Nussenblatt, Robert; Ferris, Frederick; Meyerle, CatherineGraefe's Archive for Clinical and Experimental Ophthalmology (2013), 251 (12), 2705-2709CODEN: GACODL; ISSN:0721-832X. (Springer)Background: Recent evidence suggests that neovascular age-related macular degeneration (AMD) may have an immune mediated component. Palomid 529, an investigational medication involving the immune Akt/mTOR pathway, is unique in dissocg. both targets of rapamycin complexes TORC1 and TORC2. This small short-term pilot study assesses the safety of subconjunctival Palomid 529 in the treatment of neovascular AMD, with some limited efficacy information. Methods: In this 12-wk phase I open-label prospective pilot study, five participants with neovascular age-related macular degeneration that were refractory to intravitreal anti-vascular endothelial growth factor (VEGF) received three serial monthly subconjunctival doses of 1.9 mg Palomid 529. All participants were also offered concomitant monthly intravitreal anti-VEGF injections. Safety was monitored via adverse events recording. Addnl. outcome measures included visual acuity, optical coherence tomog., fluorescein angiog., indocyanine green angiog. and fundus photog. Results: The study drug was well-tolerated by all participants. There were no drug-related adverse events and no serious adverse events. A depot formed at the injection site, which persisted at the end of the study. In these anti-VEGF refractory patients, no clin. important changes in best-cor. visual acuity, fluorescein leakage pattern, choroidal neovascularization size on indocyanine green angiog., or autofluorescence pattern on fundus autofluorescence were obsd. compared to baseline. The fluid status, assessed with optical coherence tomog. showed that central retinal thickness and macular vol. remained stable in three participants, while the other two participants clin. progressed. Conclusions: Serial subconjunctival injections of Palomid 529 were well-tolerated and resulted in depot formation. There were no concerns for any ocular or systemic toxicity during this small short-term study. Larger randomized studies are required to det. efficacy.
- 93Mortensen, D. S.; Perrin-Ninkovic, S. M.; Shevlin, G.; Zhao, J.; Packard, G.; Bahmanyar, S.; Correa, M.; Elsner, J.; Harris, R.; Lee, B. G.; Papa, P.; Parnes, J. S.; Riggs, J. R.; Sapienza, J.; Tehrani, L.; Whitefield, B.; Apuy, J.; Bisonette, R. R.; Gamez, J. C.; Hickman, M.; Khambatta, G.; Leisten, J.; Peng, S. X.; Richardson, S. J.; Cathers, B. E.; Canan, S. S.; Moghaddam, M. F.; Raymon, H. K.; Worland, P.; Narla, R. K.; Fultz, K. E.; Sankar, S. Discovery of mammalian target of rapamycin (mTOR) kinase inhibitor CC-223. J. Med. Chem. 2015, 58, 5323– 5333, DOI: 10.1021/acs.jmedchem.5b00626[ACS Full Text], [CAS], Google Scholar93https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVansrzI&md5=0f1ed6d929618ea8468fefefb196c606Discovery of Mammalian Target of Rapamycin (mTOR) Kinase Inhibitor CC-223Mortensen, Deborah S.; Perrin-Ninkovic, Sophie M.; Shevlin, Graziella; Zhao, Jingjing; Packard, Garrick; Bahmanyar, Sogole; Correa, Matthew; Elsner, Jan; Harris, Roy; Lee, Branden G. S.; Papa, Patrick; Parnes, Jason S.; Riggs, Jennifer R.; Sapienza, John; Tehrani, Lida; Whitefield, Brandon; Apuy, Julius; Bisonette, Rene R.; Gamez, James C.; Hickman, Matt; Khambatta, Godrej; Leisten, Jim; Peng, Sophie X.; Richardson, Samantha J.; Cathers, Brian E.; Canan, Stacie S.; Moghaddam, Mehran F.; Raymon, Heather K.; Worland, Peter; Narla, Rama Krishna; Fultz, Kimberly E.; Sankar, SabitaJournal of Medicinal Chemistry (2015), 58 (13), 5323-5333CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)We report here the synthesis and structure-activity relationship (SAR) of a novel series of mammalian target of rapamycin (mTOR) kinase inhibitors. A series of 4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones were optimized for in vivo efficacy. These efforts resulted in the identification of compds. with excellent mTOR kinase inhibitory potency, with exquisite kinase selectivity over the related lipid kinase PI3K. The improved PK properties of this series allowed for exploration of in vivo efficacy and ultimately the selection of CC-223, I, for clin. development.
- 94Toker, A.; Cantley, L. C. Signalling through the lipid products of phosphoinositide-3-OH kinase. Nature 1997, 387, 673– 676, DOI: 10.1038/42648[Crossref], [PubMed], [CAS], Google Scholar94https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXktVWgt7c%253D&md5=9c0d3fdb3a9a10027050c09ed3def89aSignalling through the lipid products of phosphoinositide-3-OH kinaseToker, Alex; Cantley, Lewis C.Nature (London) (1997), 387 (6634), 673-676CODEN: NATUAS; ISSN:0028-0836. (Macmillan Magazines)A review, with 47 refs. When a stimulatory agonist mol. binds at the exterior of the cell membrane, a second messenger transduces the signal to the interior of the cell. Second messengers can be derived from phospholipids in the membrane by the action of the enzymes phospholipase C or phosphoinositide-3-OH kinase (PI(3)K). PI(3)K is a key player in many cellular responses, including the movement of organelle membranes, shape alteration through rearrangement of cytoskeletal actin, transformation and chemotaxis. But how PI(3)K mediates these responses is only now becoming clear.
- 95Engelman, J. A. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat. Rev. Cancer 2009, 9, 550– 562, DOI: 10.1038/nrc2664[Crossref], [PubMed], [CAS], Google Scholar95https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXovFylsrg%253D&md5=f0d4cc1fabf879e95f8b76e48cc9c1adTargeting PI3K signalling in cancer: opportunities, challenges and limitationsEngelman, Jeffrey A.Nature Reviews Cancer (2009), 9 (8), 550-562CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)A review. There are ample genetic and lab. studies that suggest the PI3K-Akt pathway is vital to the growth and survival of cancer cells. Inhibitors targeting this pathway are entering the clinic at a rapid pace. In this Review, the therapeutic potential of drugs targeting PI3K-Akt signaling for the treatment of cancer is discussed. I focus on the advantages and drawbacks of different treatment strategies for targeting this pathway, the cancers that might respond best to these therapies and the challenges and limitations that confront their clin. development.
- 96Zhao, W.; Qiu, Y.; Kong, D. Class I phosphatidylinositol 3-kinase inhibitors for cancer therapy. Acta Pharm. Sin. B 2017, 7, 27– 37, DOI: 10.1016/j.apsb.2016.07.006[Crossref], [PubMed], [CAS], Google Scholar96https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1c7ovFOrsg%253D%253D&md5=9506d6088eb6f72dc579ece97bb19930Class I phosphatidylinositol 3-kinase inhibitors for cancer therapyZhao Wennan; Qiu Yuling; Kong DexinActa pharmaceutica Sinica. B (2017), 7 (1), 27-37 ISSN:2211-3835.The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in human cancers. Class I PI3Ks are lipid kinases that phosphorylate phosphatidylinositol 4,5-bisphosphate (PIP2) at the 3-OH of the inositol ring to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3), which in turn activates Akt and the downstream effectors like mammalian target of rapamycin (mTOR) to play key roles in carcinogenesis. Therefore, PI3K has become an important anticancer drug target, and currently there is very high interest in the pharmaceutical development of PI3K inhibitors. Idelalisib has been approved in USA and Europe as the first-in-class PI3K inhibitor for cancer therapy. Dozens of other PI3K inhibitors including BKM120 and ZSTK474 are being evaluated in clinical trials. Multifaceted studies on these PI3K inhibitors are being performed, such as single and combinational efficacy, resistance, biomarkers, etc. This review provides an introduction to PI3K and summarizes key advances in the development of PI3K inhibitors.
- 97Garces, A. E.; Stocks, M. J. Class 1 PI3K clinical candidates and recent inhibitor design strategies: a medicinal chemistry perspective. J. Med. Chem. 2019, 62, 4815– 4850, DOI: 10.1021/acs.jmedchem.8b01492[ACS Full Text], [CAS], Google Scholar97https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFOku7bK&md5=907395a39ed6fb683464ee92c6a2537fClass 1 PI3K Clinical Candidates and Recent Inhibitor Design Strategies: A Medicinal Chemistry PerspectiveGarces, Aimie E.; Stocks, Michael J.Journal of Medicinal Chemistry (2019), 62 (10), 4815-4850CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Phosphatidylinositol 3-kinases (PI3Ks) are a family of lipid kinases that phosphorylate the 3-OH of the inositol ring of phosphoinositides, and deregulation of this pathway has implications in many diseases. The search for novel PI3K inhibitors has been at the forefront of academic and industrial medicinal chem. with over 600 medicinal chem.-based publications and patents appearing to date, leading to 38 clin. candidates and the launch of two drugs, idelalisib in 2014 and copanlisib in 2017. This Perspective will discuss medicinal chem. design approaches to novel isoform-selective inhibitors through consideration of brief case histories of compds. that have progressed into clin. development or that have revealed new structural motifs in this highly competitive area of research.
- 98Down, K.; Amour, A.; Baldwin, I. R.; Cooper, A. W.; Deakin, A. M.; Felton, L. M.; Guntrip, S. B.; Hardy, C.; Harrison, Z. A.; Jones, K. L.; Jones, P.; Keeling, S. E.; Le, J.; Livia, S.; Lucas, F.; Lunniss, C. J.; Parr, N. J.; Robinson, E.; Rowland, P.; Smith, S.; Thomas, D. A.; Vitulli, G.; Washio, Y.; Hamblin, J. N. Optimization of novel indazoles as highly potent and selective inhibitors of Phosphoinositide 3-kinase δ for the treatment of respiratory disease. J. Med. Chem. 2015, 58, 7381– 7399, DOI: 10.1021/acs.jmedchem.5b00767[ACS Full Text], [CAS], Google Scholar98https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtlyjsrvJ&md5=2fe8e51a64e6f7c798bdcb63781d02adOptimization of Novel Indazoles as Highly Potent and Selective Inhibitors of Phosphoinositide 3-Kinase δ for the Treatment of Respiratory DiseaseDown, Kenneth; Amour, Augustin; Baldwin, Ian R.; Cooper, Anthony W. J.; Deakin, Angela M.; Felton, Leigh M.; Guntrip, Stephen B.; Hardy, Charlotte; Harrison, Zoe A.; Jones, Katherine L.; Jones, Paul; Keeling, Suzanne E.; Le, Joelle; Livia, Stefano; Lucas, Fiona; Lunniss, Christopher J.; Parr, Nigel J.; Robinson, Ed; Rowland, Paul; Smith, Sarah; Thomas, Daniel A.; Vitulli, Giovanni; Washio, Yoshiaki; Hamblin, J. NicoleJournal of Medicinal Chemistry (2015), 58 (18), 7381-7399CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Optimization of lead compd., through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clin. candidates I (GSK2269557) and II (GSK2292767) for the treatment of respiratory indications via inhalation. Compds. I and II are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation.
- 99Berndt, A.; Miller, S.; Williams, O.; Le, D. D; Houseman, B. T; Pacold, J. I; Gorrec, F.; Hon, W.-C.; Ren, P.; Liu, Y.; Rommel, C.; Gaillard, P.; Ruckle, T.; Schwarz, M. K; Shokat, K. M; Shaw, J. P; Williams, R. L The p110delta structure: mechanisms for selectivity and potency of new PI(3)K inhibitors. Nat. Chem. Biol. 2010, 6, 244, DOI: 10.1038/nchembio0310-244b[Crossref], [PubMed], [CAS], Google Scholar99https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhvFGnurk%253D&md5=9220d9d2eda6bdb3bc9e54437dfcff23The p110δ structure: mechanisms for selectivity and potency of new PI(3)K inhibitors. [Erratum to document cited in CA152:375583]Berndt, Alex; Miller, Siimon; Williams, Olusegun; Le, Daniel D.; Houseman, Benjamin T.; Pacold, Joseph I.; Gorrec, Fabrice; Hon, Wai-Chon; Liu, Yi; Rommel, Christian; Gaillard, Pascale; Rueckle, Thomas; Schwarz, Matthias K.; Shokat, Kevan M.; Shaw, Jeffrey P.; Williams, Roger L.Nature Chemical Biology (2010), 6 (3), 244CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)On page 117, in the author list, Pingda Ren, was omitted. The error has been cor. in the author list, author contributions and conflict of financial interest declaration in the HTML and PDF versions.
- 100Helmer, E.; Watling, M.; Jones, E.; Tytgat, D.; Jones, M.; Allen, R.; Payne, A.; Koch, A.; Healy, E. First-in-human studies of seletalisib, an orally bioavailable small-molecule PI3Kδ inhibitor for the treatment of immune and inflammatory diseases. Eur. J. Clin. Pharmacol. 2017, 73, 581– 591, DOI: 10.1007/s00228-017-2205-7[Crossref], [PubMed], [CAS], Google Scholar100https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXitFCrtLw%253D&md5=362235b5549c53252f30d4a3dd1c744eFirst-in-human studies of seletalisib, an orally bioavailable small-molecule PI3Kδ inhibitor for the treatment of immune and inflammatory diseasesHelmer, Eric; Watling, Mark; Jones, Emma; Tytgat, Dominique; Jones, Mark; Allen, Rodger; Payne, Andrew; Koch, Annelize; Healy, EugeneEuropean Journal of Clinical Pharmacology (2017), 73 (5), 581-591CODEN: EJCPAS; ISSN:0031-6970. (Springer)Purpose: PI3Ks are potential therapeutic targets in immune-inflammatory diseases. These studies aimed to investigate the safety, tolerability and PK profile of seletalisib, a selective inhibitor of PI3Kδ in humans. Methods: These phase I, randomized, double-blind, placebo-controlled, single-center studies (NCT02303509, NCT02207595) evaluated single and multiple oral doses of seletalisib (5-90 mg QD and 30 mg BID) in healthy adults and subjects with mild-to-moderate psoriasis (Study-1). Pharmacodynamic effects on markers of inflammation were assessed via changes in ex vivo basophil degranulation and histol. assessment of psoriatic skin biopsies. Results: Seletalisib was well tolerated at doses ≤15 mg (Study-1) and ≤45 mg QD (Study-2) for 14 days. No safety concerns or dose-limiting toxicities were identified (Study-1). Incidence of gastrointestinal-related AEs was not dose related but higher incidences of rash AEs were assocd. with higher-dose seletalisib (Study-2 rash AEs: 18 in 12 seletalisib-treated subjects vs. 1 in 1 placebo-treated subject). Mean seletalisib plasma concn.-time profiles increased with increasing doses after single and multiple dosing, with no major deviations from dose-proportionality. There was no unexpected accumulation or loss of exposure after multiple dosing (time-independent pharmacokinetic profile). Apparent t1/2 values were supportive of once-daily dosing (geometric mean t1/2: Study-1, 17.7-21.1 h; Study-2, 18.1-22.4 h). No clin. significant food effect was obsd. (Study-1). Pharmacodynamic findings demonstrated ex vivo inhibition of basophil degranulation, improvements in histol. assessment of skin biopsies and other markers of psoriatic biol. and preliminary evidence of target engagement in psoriatic skin tissue. Conclusions: Seletalisib safety, tolerability and pharmacokinetic/pharmacodynamic profiles support its continued clin. development in immune-inflammatory diseases.
- 101Rao, V. K.; Webster, S.; Dalm, V.; Sediva, A.; van Hagen, P. M.; Holland, S.; Rosenzweig, S. D.; Christ, A. D.; Sloth, B.; Cabanski, M.; Joshi, A. D.; de Buck, S.; Doucet, J.; Guerini, D.; Kalis, C.; Pylvaenaeinen, I.; Soldermann, N.; Kashyap, A.; Uzel, G.; Lenardo, M. J.; Patel, D. D.; Lucas, C. L.; Burkhart, C. Effective “activated PI3Kδ syndrome“-targeted therapy with the PI3Kδ inhibitor leniolisib. Blood 2017, 130, 2307– 2316, DOI: 10.1182/blood-2017-08-801191[Crossref], [PubMed], [CAS], Google Scholar101https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhs1erurnE&md5=cc03232e6fe6b27a3aad988755fb0fc6Effective "activated PI3Kδ syndrome"-targeted therapy with the PI3Kδ inhibitor leniolisibRao, V. Koneti; Webster, Sharon; Dalm, Virgil A. S. H.; Sediva, Anna; van Hagen, P. Martin; Holland, Steven; Rosenzweig, Sergio D.; Christ, Andreas D.; Sloth, Birgitte; Cabanski, Maciej; Joshi, Aniket D.; de Buck, Stefan; Doucet, Julie; Guerini, Danilo; Kalis, Christoph; Pylvaenaeinen, Ilona; Soldermann, Nicolas; Kashyap, Anuj; Uzel, Gulbu; Lenardo, Michael J.; Patel, Dhavalkumar D.; Lucas, Carrie L.; Burkhart, ChristophBlood (2017), 130 (21), 2307-2316CODEN: BLOOAW; ISSN:1528-0020. (American Society of Hematology)Pathogenic gain-of-function variants in the genes encoding phosphoinositide 3-kinase δ (PI3Kδ) lead to accumulation of transitional B cells and senescent T cells, lymphadenopathy, and immune deficiency (activated PI3Kδ syndrome [APDS]). Knowing the genetic etiol. of APDS afforded us the opportunity to explore PI3Kδ inhibition as a precision-medicine therapy. Here, we report in vitro and in vivo effects of inhibiting PI3Kδ in APDS. Treatment with leniolisib (CDZ173), a selective PI3Kδ inhibitor, caused dose-dependent suppression of PI3Kδ pathway hyperactivation (measured as phosphorylation of AKT/S6) in cell lines ectopically expressing APDS-causative p110δ variants and in T-cell blasts derived from patients. A clin. trial with 6 APDS patients was conducted as a 12-wk, open-label, multisite, within-subject, dose-escalation study of oral leniolisib to assess safety, pharmacokinetics, and effects on lymphoproliferation and immune dysregulation. Oral leniolisib led to a dose-dependent redn. in PI3K/AKT pathway activity assessed ex vivo and improved immune dysregulation. We obsd. normalization of circulating transitional and naive B cells, redn. in PD-1+CD4+ and senescent CD57+CD4- T cells, and decreases in elevated serum IgM and inflammatory markers including interferon γ, tumor necrosis factor, CXCL13, and CXCL10 with leniolisib therapy. After 12 wk of treatment, all patients showed amelioration of lymphoproliferation with lymph node sizes and spleen vols. reduced by 39% (mean; range, 26%-57%) and 40% (mean; range, 13%-65%), resp. Thus, leniolisib was well tolerated and improved lab. and clin. parameters in APDS, supporting the specific inhibition of PI3Kδ as a promising new targeted therapy in APDS and other diseases characterized by overactivation of the PI3Kδ pathway.
- 102Greenwell, I. B.; Ip, A.; Cohen, J. B. PI3K inhibitors: understanding toxicity mechanisms and management. Oncology (Williston Park) 2017, 31, 821– 828[PubMed], [CAS], Google Scholar102https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1M3ltlGntA%253D%253D&md5=6c477dd4ae70ee2393283cd0b43ec885PI3K Inhibitors: Understanding Toxicity Mechanisms and ManagementGreenwell I Brian; Ip Andrew; Cohen Jonathon BOncology (Williston Park, N.Y.) (2017), 31 (11), 821-8 ISSN:0890-9091.The phosphatidylinositol 3-kinase (PI3K) pathway has attracted immense interest as a therapeutic target for cancer treatment. Idelalisib was the first PI3K inhibitor approved by the US Food and Drug Administration and is utilized in the treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma. Copanlisib has subsequently been approved for relapsed follicular lymphoma in patients who have received at least two prior systemic therapies. There are multiple other PI3K agents currently in development; these target various combinations of PI3K isoforms. Despite the therapeutic benefit, there have been concerns about the severe and sometimes fatal adverse effects of this class of drug. Several side effects are unusual and have poorly understood mechanisms; these include autoimmune dysfunction, opportunistic infections, skin toxicity, hypertension, and hyperglycemia. An understanding of these unusual toxicities, as well as a good grasp of management principles, will be important as more PI3K inhibitors are approved and become incorporated into routine practice.
- 103Evans, C. A.; Liu, T.; Lescarbeau, A.; Nair, S. J.; Grenier, L.; Pradeilles, J. A.; Glenadel, Q.; Tibbitts, T.; Rowley, A. M.; DiNitto, J. P.; Brophy, E. E.; O’Hearn, E. L.; Ali, J. A.; Winkler, D. G.; Goldstein, S. I.; O’Hearn, P.; Martin, C. M.; Hoyt, J. G.; Soglia, J. R.; Cheung, C.; Pink, M. M.; Proctor, J. L.; Palombella, V. J.; Tremblay, M. R.; Castro, A. C. Discovery of a selective Phosphoinositide-3-kinase (PI3K)-γ inhibitor (IPI-549) as an immuno-oncology clinical candidate. ACS Med. Chem. Lett. 2016, 7, 862– 867, DOI: 10.1021/acsmedchemlett.6b00238[ACS Full Text], [CAS], Google Scholar103https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1aju7vO&md5=9850bb40b0727512d0ca844264c2ec8aDiscovery of a Selective Phosphoinositide-3-Kinase (PI3K)-γ Inhibitor (IPI-549) as an Immuno-Oncology Clinical CandidateEvans, Catherine A.; Liu, Tao; Lescarbeau, Andre; Nair, Somarajan J.; Grenier, Louis; Pradeilles, Johan A.; Glenadel, Quentin; Tibbitts, Thomas; Rowley, Ann M.; DiNitto, Jonathan P.; Brophy, Erin E.; OHearn, Erin L.; Ali, Janid A.; Winkler, David G.; Goldstein, Stanley I.; OHearn, Patrick; Martin, Christian M.; Hoyt, Jennifer G.; Soglia, John R.; Cheung, Culver; Pink, Melissa M.; Proctor, Jennifer L.; Palombella, Vito J.; Tremblay, Martin R.; Castro, Alfredo C.ACS Medicinal Chemistry Letters (2016), 7 (9), 862-867CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Optimization of isoquinolinone PI3K inhibitors led to the discovery of a potent inhibitor of PI3K-γ (IPI-549) with >100-fold selectivity over other lipid and protein kinases. IPI-549 demonstrates favorable pharmacokinetic properties and robust inhibition of PI3K-γ mediated neutrophil migration in vivo and is currently in Phase 1 clin. evaluation in subjects with advanced solid tumors.
- 104Lin, S.; Jin, J.; Liu, Y.; Tian, H.; Zhang, Y.; Fu, R.; Zhang, J.; Wang, M.; Du, T.; Ji, M.; Wu, D.; Zhang, K.; Sheng, L.; Li, Y.; Chen, X.; Xu, H. Discovery of 4-methylquinazoline based PI3K inhibitors for the potential treatment of idiopathic pulmonary fibrosis. J. Med. Chem. 2019, 62, 8873– 8879, DOI: 10.1021/acs.jmedchem.9b00969[ACS Full Text], [CAS], Google Scholar104https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVemu7jI&md5=63e1f5f4ecd6796f77ee3885f10a8823Discovery of 4-Methylquinazoline Based PI3K Inhibitors for the Potential Treatment of Idiopathic Pulmonary FibrosisLin, Songwen; Jin, Jing; Liu, Ying; Tian, Hua; Zhang, Yan; Fu, Rong; Zhang, Jingbo; Wang, Mingjin; Du, Tingting; Ji, Ming; Wu, Deyu; Zhang, Kehui; Sheng, Li; Li, Yan; Chen, Xiaoguang; Xu, HengJournal of Medicinal Chemistry (2019), 62 (19), 8873-8879CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease, and its mol. pathogenesis remains poorly understood. Recently, emerging evidence demonstrates that the PI3K signaling transduction pathway is linked to the pathol. of IPF. In this work, we rationally designed a new series of 4-methylquinazoline derivs. as highly potent PI3K inhibitors that significantly suppress the phosphorylation of the main PI3K downstream effectors and displays marked antiproliferative activity in mouse MLg2908 lung fibroblasts. In a bleomycin-induced mouse pulmonary fibrosis model, 5d from the series improved mouse lung function and slowed the progression of pulmonary fibrosis. Overall, this work promises a therapeutic potential for PI3K inhibitors to treat IPF.
- 105Come, J. H.; Collier, P. N.; Henderson, J. A.; Pierce, A. C.; Davies, R. J.; Le Tiran, A.; O’Dowd, H.; Bandarage, U. K.; Cao, J.; Deininger, D.; Grey, R.; Krueger, E. B.; Lowe, D. B.; Liang, J.; Liao, Y.; Messersmith, D.; Nanthakumar, S.; Sizensky, E.; Wang, J.; Xu, J.; Chin, E. Y.; Damagnez, V.; Doran, J. D.; Dworakowski, W.; Griffith, J. P.; Jacobs, M. D.; Khare-Pandit, S.; Mahajan, S.; Moody, C. S.; Aronov, A. M. Design and synthesis of a novel series of orally bioavailable, CNS-penetrant, isoform selective Phosphoinositide 3-kinase γ (PI3Kγ) inhibitors with potential for the treatment of multiple sclerosis (MS). J. Med. Chem. 2018, 61, 5245– 5256, DOI: 10.1021/acs.jmedchem.8b00085[ACS Full Text], [CAS], Google Scholar105https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVGjsr%252FP&md5=6cae03cd2a64df22832dbdb29ceb0d7cDesign and Synthesis of a Novel Series of Orally Bioavailable, CNS-Penetrant, Isoform Selective Phosphoinositide 3-Kinase γ (PI3Kγ) Inhibitors with Potential for the Treatment of Multiple Sclerosis (MS)Come, Jon H.; Collier, Philip N.; Henderson, James A.; Pierce, Albert C.; Davies, Robert J.; Le Tiran, Arnaud; O'Dowd, Hardwin; Bandarage, Upul K.; Cao, Jingrong; Deininger, David; Grey, Ron; Krueger, Elaine B.; Lowe, Derek B.; Liang, Jianglin; Liao, Yusheng; Messersmith, David; Nanthakumar, Suganthi; Sizensky, Emmanuelle; Wang, Jian; Xu, Jinwang; Chin, Elaine Y.; Damagnez, Veronique; Doran, John D.; Dworakowski, Wojciech; Griffith, James P.; Jacobs, Marc D.; Khare-Pandit, Suvarna; Mahajan, Sudipta; Moody, Cameron S.; Aronov, Alex M.Journal of Medicinal Chemistry (2018), 61 (12), 5245-5256CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The lipid kinase phosphoinositide 3-kinase γ (PI3Kγ) has attracted attention as a potential target to treat a variety of autoimmune disorders, including multiple sclerosis, due to its role in immune modulation and microglial activation. By minimizing the no. of hydrogen bond donors while targeting a previously uncovered selectivity pocket adjacent to the ATP binding site of PI3Kγ, we discovered a series of azaisoindolinones as selective, brain penetrant inhibitors of PI3Kγ. This ultimately led to the discovery of 16, an orally bioavailable compd. that showed efficacy in murine exptl. autoimmune encephalomyelitis (EAE), a preclin. model of multiple sclerosis.
- 106Erra, M.; Taltavull, J.; Bernal, F. J.; Caturla, J. F.; Carrascal, M.; Pages, L.; Mir, M.; Espinosa, S.; Gracia, J.; Dominguez, M.; Sabate, M.; Paris, S.; Maldonado, M.; Hernandez, B.; Bravo, M.; Calama, E.; Miralpeix, M.; Lehner, M. D.; Calbet, M. Discovery of a novel inhaled PI3Kδ inhibitor for the treatment of respiratory diseases. J. Med. Chem. 2018, 61, 9551– 9567, DOI: 10.1021/acs.jmedchem.8b00873[ACS Full Text], [CAS], Google Scholar106https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvFaltbbK&md5=f7f14dd277a8ef119a2aeabb1558a838Discovery of a Novel Inhaled PI3Kδ Inhibitor for the Treatment of Respiratory DiseasesErra, Montse; Taltavull, Joan; Bernal, Francisco Javier; Caturla, Juan Francisco; Carrascal, Marta; Pages, Lluis; Mir, Marta; Espinosa, Sonia; Gracia, Jordi; Dominguez, Maria; Sabate, Mar; Paris, Stephane; Maldonado, Monica; Hernandez, Begona; Bravo, Monica; Calama, Elena; Miralpeix, Montserrat; Lehner, Martin D.; Calbet, MartaJournal of Medicinal Chemistry (2018), 61 (21), 9551-9567CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Oral PI3Kδ inhibitors such as Idelalisib and Duvelisib have shown efficacy as anticancer agents and Idelalisib has been approved for the treatment of three B-cell cancers. However, Idelalisib has a black box warning on its product label regarding the risks of fatal and serious toxicities including hepatic toxicity, severe diarrhea, colitis, pneumonitis, infections, and intestinal perforation. Some of these side effects are mechanism-related and could hinder the development of Idelalisib for less severe conditions. For respiratory diseases, compds. administered by inhalation are delivered directly to the site of action and may improve the therapeutic index of a drug, minimizing undesired side effects. This work describes the discovery and optimization of inhaled PI3Kδ inhibitors intended for the treatment of severe asthma and COPD. Once the potency was in the desired range, efforts were focused on identifying the particular physicochem. properties that could translate into better lung retention. This medicinal chem. exercise led to the identification of LAS195319 as a candidate for clin. development.
- 107Liu, Q.; Shi, Q.; Marcoux, D.; Batt, D. G.; Cornelius, L.; Qin, L. Y.; Ruan, Z.; Neels, J.; Beaudoin-Bertrand, M.; Srivastava, A. S.; Li, L.; Cherney, R. J.; Gong, H.; Watterson, S. H.; Weigelt, C.; Gillooly, K. M.; McIntyre, K. W.; Xie, J. H.; Obermeier, M. T.; Fura, A.; Sleczka, B.; Stefanski, K.; Fancher, R. M.; Padmanabhan, S.; Rp, T.; Kundu, I.; Rajareddy, K.; Smith, R.; Hennan, J. K.; Xing, D.; Fan, J.; Levesque, P. C.; Ruan, Q.; Pitt, S.; Zhang, R.; Pedicord, D.; Pan, J.; Yarde, M.; Lu, H.; Lippy, J.; Goldstine, C.; Skala, S.; Rampulla, R. A.; Mathur, A.; Gupta, A.; Arunachalam, P. N.; Sack, J. S.; Muckelbauer, J. K.; Cvijic, M. E.; Salter-Cid, L. M.; Bhide, R. S.; Poss, M. A.; Hynes, J.; Carter, P. H.; Macor, J. E.; Ruepp, S.; Schieven, G. L.; Tino, J. A. Identification of a potent, selective, and efficacious Phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitor for the treatment of immunological disorders. J. Med. Chem. 2017, 60, 5193– 5208, DOI: 10.1021/acs.jmedchem.7b00618[ACS Full Text], [CAS], Google Scholar107https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXos1Sgtbc%253D&md5=4bcbe85e7b82c19e47065be4fbeccdc8Identification of a Potent, Selective, and Efficacious Phosphatidylinositol 3-Kinase δ (PI3Kδ) Inhibitor for the Treatment of Immunological DisordersLiu, Qingjie; Shi, Qing; Marcoux, David; Batt, Douglas G.; Cornelius, Lyndon; Qin, Lan-Ying; Ruan, Zheming; Neels, James; Beaudoin-Bertrand, Myra; Srivastava, Anurag S.; Li, Ling; Cherney, Robert J.; Gong, Hua; Watterson, Scott H.; Weigelt, Carolyn; Gillooly, Kathleen M.; McIntyre, Kim W.; Xie, Jenny H.; Obermeier, Mary T.; Fura, Aberra; Sleczka, Bogdan; Stefanski, Kevin; Fancher, R. M.; Padmanabhan, Shweta; Thatipamula, R. P.; Kundu, Ipsit; Rajareddy, Kallem; Smith, Rodney; Hennan, James K.; Xing, Dezhi; Fan, Jingsong; Levesque, Paul C.; Ruan, Qian; Pitt, Sidney; Zhang, Rosemary; Pedicord, Donna; Pan, Jie; Yarde, Melissa; Lu, Hao; Lippy, Jonathan; Goldstine, Christine; Skala, Stacey; Rampulla, Richard A.; Mathur, Arvind; Gupta, Anuradha; Arunachalam, Pirama Nayagam; Sack, John S.; Muckelbauer, Jodi K.; Cvijic, Mary Ellen; Salter-Cid, Luisa M.; Bhide, Rajeev S.; Poss, Michael A.; Hynes, John; Carter, Percy H.; Macor, John E.; Ruepp, Stefan; Schieven, Gary L.; Tino, Joseph A.Journal of Medicinal Chemistry (2017), 60 (12), 5193-5208CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)PI3Kδ plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunol. disorders. This article highlights the work toward the identification of a potent, selective, and efficacious PI3Kδ inhibitor. Through careful SAR, the successful replacement of a polar pyrazole group by a simple chloro or trifluoromethyl group led to improved Caco-2 permeability, reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity profile while maintaining potency in the CD69 hWB assay. The optimization of the aryl substitution then identified a 4'-CN group that improved the human/rodent correlation in microsomal metabolic stability. The lead mol. is very potent in PK/PD assays and highly efficacious in a mouse collagen-induced arthritis model.
- 108Amour, A.; Barton, N.; Cooper, A. W.; Inglis, G.; Jamieson, C.; Luscombe, C. N.; Morrell, J.; Peace, S.; Perez, D.; Rowland, P.; Tame, C. J.; Uddin, S.; Vitulli, G.; Wellaway, N. Evolution of a novel, orally bioavailable series of PI3Kδ inhibitors from an inhaled lead for the treatment of respiratory disease. J. Med. Chem. 2016, 59, 7239– 7251, DOI: 10.1021/acs.jmedchem.6b00799[ACS Full Text], [CAS], Google Scholar108https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFyitLnN&md5=ab4641778d1c80f0dd9551d6d75ff4efEvolution of a Novel, Orally Bioavailable Series of PI3Kδ Inhibitors from an Inhaled Lead for the Treatment of Respiratory DiseaseAmour, Augustin; Barton, Nick; Cooper, Anthony W. J.; Inglis, Graham; Jamieson, Craig; Luscombe, Christopher N.; Morrell, Josie; Peace, Simon; Perez, David; Rowland, Paul; Tame, Christopher J.; Uddin, Sorif; Vitulli, Giovanni; Wellaway, NatalieJournal of Medicinal Chemistry (2016), 59 (15), 7239-7251CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A four-step process of high-quality modeling of existing data, deconstruction, identification of replacement cores, and an innovative synthetic regrowth strategy led to the rapid discovery of a novel oral series of PI3Kδ inhibitors with promising selectivity and excellent in vivo characteristics.
- 109Shin, Y.; Suchomel, J.; Cardozo, M.; Duquette, J.; He, X.; Henne, K.; Hu, Y. L.; Kelly, R. C.; McCarter, J.; McGee, L. R.; Medina, J. C.; Metz, D.; San Miguel, T.; Mohn, D.; Tran, T.; Vissinga, C.; Wong, S.; Wannberg, S.; Whittington, D. A.; Whoriskey, J.; Yu, G.; Zalameda, L.; Zhang, X.; Cushing, T. D. Discovery, optimization, and in vivo evaluation of benzimidazole derivatives AM-8508 and AM-9635 as potent and selective PI3Kδ inhibitors. J. Med. Chem. 2016, 59, 431– 447, DOI: 10.1021/acs.jmedchem.5b01651[ACS Full Text], [CAS], Google Scholar109https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvFylurnP&md5=258ce4cf8c13cf799f342ebab3137264Discovery, Optimization, and in Vivo Evaluation of Benzimidazole Derivatives AM-8508 and AM-9635 as Potent and Selective PI3Kδ InhibitorsShin, Youngsook; Suchomel, Julia; Cardozo, Mario; Duquette, Jason; He, Xiao; Henne, Kirk; Hu, Yi-Ling; Kelly, Ron C.; McCarter, John; McGee, Lawrence R.; Medina, Julio C.; Metz, Daniela; San Miguel, Tisha; Mohn, Deanna; Tran, Thuy; Vissinga, Christine; Wong, Simon; Wannberg, Sharon; Whittington, Douglas A.; Whoriskey, John; Yu, Gang; Zalameda, Leeanne; Zhang, Xuxia; Cushing, Timothy D.Journal of Medicinal Chemistry (2016), 59 (1), 431-447CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Lead optimization efforts resulted in the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, 1 (AM-8508) and 2 (AM-9635), with good pharmacokinetic properties. The compds. inhibit B cell receptor (BCR)-mediated AKT phosphorylation (pAKT) in PI3Kδ-dependent in vitro cell based assays. These compds. which share a benzimidazole bicycle are effective when administered in vivo at unbound concns. consistent with their in vitro cell potency as a consequence of improved unbound drug concn. with lower unbound clearance. Furthermore, the compds. demonstrated efficacy in a Keyhole Limpet Hemocyanin (KLH) study in rats, where the blockade of PI3Kδ activity by inhibitors 1 and 2 led to effective inhibition of antigen-specific IgG and IgM formation after immunization with KLH.
- 110Xu, F.; Na, L.; Li, Y.; Chen, L. Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours. Cell Biosci. 2020, 10, 54, DOI: 10.1186/s13578-020-00416-0[Crossref], [PubMed], [CAS], Google Scholar110https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB38zivVSktQ%253D%253D&md5=fc383947b2d3516bf4691cca2b4b8804Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumoursXu Fei; Xu Fei; Na Lixin; Na Lixin; Li Yanfei; Chen LinjunCell & bioscience (2020), 10 (), 54 ISSN:2045-3701.The PI3 K/AKT/mTOR signalling pathway plays an important role in the regulation of signal transduction and biological processes such as cell proliferation, apoptosis, metabolism and angiogenesis. Compared with those of other signalling pathways, the components of the PI3K/AKT/mTOR signalling pathway are complicated. The regulatory mechanisms and biological functions of the PI3K/AKT/mTOR signalling pathway are important in many human diseases, including ischaemic brain injury, neurodegenerative diseases, and tumours. PI3K/AKT/mTOR signalling pathway inhibitors include single-component and dual inhibitors. Numerous PI3K inhibitors have exhibited good results in preclinical studies, and some have been clinically tested in haematologic malignancies and solid tumours. In this review, we briefly summarize the results of research on the PI3K/AKT/mTOR pathway and discuss the structural composition, activation, communication processes, regulatory mechanisms and biological functions of the PI3K/AKT/mTOR signalling pathway in the pathogenesis of neurodegenerative diseases and tumours.
- 111Sun, K.; Luo, J.; Guo, J.; Yao, X.; Jing, X.; Guo, F. The PI3K/AKT/mTOR signaling pathway in osteoarthritis: a narrative review. Osteoarthritis Cartilage 2020, 28, 400– 409, DOI: 10.1016/j.joca.2020.02.027[Crossref], [PubMed], [CAS], Google Scholar111https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB387ksVKrtw%253D%253D&md5=33103b1a7ddf14d7554be97386308538The PI3K/AKT/mTOR signaling pathway in osteoarthritis: a narrative reviewSun K; Guo J; Yao X; Jing X; Guo F; Luo JOsteoarthritis and cartilage (2020), 28 (4), 400-409 ISSN:.Osteoarthritis (OA) is a complicated degenerative disease that affects whole joint tissue. Currently, apart from surgical approaches to treat late stage OA, effective treatments to reverse OA are not available. Thus, the mechanisms leading to OA, and more effective approaches to treat OA should be investigated. According to available evidence, the PI3K/AKT/mTOR signaling pathway is essential for normal metabolism of joint tissues, but is also involved in development of OA. To provide a wide viewpoint to roles of PI3K/AKT/mTOR signaling pathway in osteoarthritis, a comprehensive literature search was performed using PubMed terms 'PI3K OR AKT OR mTOR' and 'osteoarthritis'. This review highlights the role of PI3K/AKT/mTOR signaling in cartilage degradation, subchondral bone dysfunction, and synovial inflammation, and discusses how this signaling pathway affects development of the disease. We also summarize recent evidences of therapeutic approaches to treat OA by targeting the PI3K/AKT/mTOR pathway, and discuss potential challenges in developing these strategies for clinical treatment of OA.
- 112Fu, R. G.; Sun, Y.; Sheng, W. B.; Liao, D. F. Designing multi-targeted agents: An emerging anticancer drug discovery paradigm. Eur. J. Med. Chem. 2017, 136, 195– 211, DOI: 10.1016/j.ejmech.2017.05.016[Crossref], [PubMed], [CAS], Google Scholar112https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnsV2rtL8%253D&md5=511561bd2cd186d5dafa905b7257bf32Designing multi-targeted agents: An emerging anticancer drug discovery paradigmFu, Rong-geng; Sun, Yuan; Sheng, Wen-bing; Liao, Duan-fangEuropean Journal of Medicinal Chemistry (2017), 136 (), 195-211CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)A review. The dominant paradigm in drug discovery is to design ligands with max. selectivity to act on individual drug targets. With the target-based approach, many new chem. entities have been discovered, developed, and further approved as drugs. However, there are a large no. of complex diseases such as cancer that cannot be effectively treated or cured only with one medicine to modulate the biol. function of a single target. As simultaneous intervention of two (or multiple) cancer progression relevant targets has shown improved therapeutic efficacy, the innovation of multi-targeted drugs has become a promising and prevailing research topic and numerous multi-targeted anticancer agents are currently at various developmental stages. However, most multi-pharmacophore scaffolds are usually discovered by serendipity or screening, while rational design by combining existing pharmacophore scaffolds remains an enormous challenge. In this review, four types of multi-pharmacophore modes are discussed, and the examples from literature will be used to introduce attractive lead compds. with the capability of simultaneously interfering with different enzyme or signaling pathway of cancer progression, which will reveal the trends and insights to help the design of the next generation multi-targeted anticancer agents.
- 113Knight, S. D.; Adams, N. D.; Burgess, J. L.; Chaudhari, A. M.; Darcy, M. G.; Donatelli, C. A.; Luengo, J. I.; Newlander, K. A.; Parrish, C. A.; Ridgers, L. H.; Sarpong, M. A.; Schmidt, S. J.; Van Aller, G. S.; Carson, J. D.; Diamond, M. A.; Elkins, P. A.; Gardiner, C. M.; Garver, E.; Gilbert, S. A.; Gontarek, R. R.; Jackson, J. R.; Kershner, K. L.; Luo, L.; Raha, K.; Sherk, C. S.; Sung, C. M.; Sutton, D.; Tummino, P. J.; Wegrzyn, R. J.; Auger, K. R.; Dhanak, D. Discovery of GSK2126458, a highly potent inhibitor of PI3K and the mammalian target of rapamycin. ACS Med. Chem. Lett. 2010, 1, 39– 43, DOI: 10.1021/ml900028r[ACS Full Text], [CAS], Google Scholar113https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmvF2qtw%253D%253D&md5=72fcca85702dba95529ac03281e0bdbcDiscovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of RapamycinKnight, Steven D.; Adams, Nicholas D.; Burgess, Joelle L.; Chaudhari, Amita M.; Darcy, Michael G.; Donatelli, Carla A.; Luengo, Juan I.; Newlander, Ken A.; Parrish, Cynthia A.; Ridgers, Lance H.; Sarpong, Martha A.; Schmidt, Stanley J.; Van Aller, Glenn S.; Carson, Jeffrey D.; Diamond, Melody A.; Elkins, Patricia A.; Gardiner, Christine M.; Garver, Eric; Gilbert, Seth A.; Gontarek, Richard R.; Jackson, Jeffrey R.; Kershner, Kevin L.; Luo, Lusong; Raha, Kaushik; Sherk, Christian S.; Sung, Chiu-Mei; Sutton, David; Tummino, Peter J.; Wegrzyn, Ronald J.; Auger, Kurt R.; Dhanak, DashyantACS Medicinal Chemistry Letters (2010), 1 (1), 39-43CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Phosphoinositide 3-kinase α (PI3Kα) is a crit. regulator of cell growth and transformation, and its signaling pathway is the most commonly mutated pathway in human cancers. The mammalian target of rapamycin (mTOR), a class IV PI3K protein kinase, is also a central regulator of cell growth, and mTOR inhibitors are believed to augment the antiproliferative efficacy of PI3K/AKT pathway inhibition. 2,4-Difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide (GSK2126458, 1 (I)) has been identified as a highly potent, orally bioavailable inhibitor of PI3Kα and mTOR with in vivo activity in both pharmacodynamic and tumor growth efficacy models. Compd. 1 is currently being evaluated in human clin. trials for the treatment of cancer.
- 114Langdon, S. P.; Kay, C.; Um, I. H.; Dodds, M.; Muir, M.; Sellar, G.; Kan, J.; Gourley, C.; Harrison, D. J. Evaluation of the dual mTOR/PI3K inhibitors Gedatolisib (PF-05212384) and PF-04691502 against ovarian cancer xenograft models. Sci. Rep. 2019, 9, 18742, DOI: 10.1038/s41598-019-55096-9[Crossref], [PubMed], [CAS], Google Scholar114https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitl2gsrzN&md5=c2044300ca0cec59fe162e5a95223ad5Evaluation of the dual mTOR/PI3K inhibitors Gedatolisib (PF-05212384) and PF-04691502 against ovarian cancer xenograft modelsLangdon, Simon P.; Kay, Charlene; Um, In Hwa; Dodds, Michael; Muir, Morwenna; Sellar, Grant; Kan, Julie; Gourley, Charlie; Harrison, David J.Scientific Reports (2019), 9 (1), 18742CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)This study investigated the antitumor effects of two dual mTOR/PI3K inhibitors, gedatolisib (WYE-129587/PKI-587/PF-05212384) and PF-04691502 against a panel of six human patient derived ovarian cancer xenograft models. Both dual mTOR/PI3K inhibitors demonstrated antitumor activity against all xenografts tested. The compds. produced tumor stasis during the treatment period and upon cessation of treatment, tumors re-grew. In several models, there was an initial rapid redn. of tumor vol. over the first week of treatment before tumor stasis. No toxicity was obsd. during treatment. Biomarker studies were conducted in two xenograft models; phospho-S6 (Ser235/236) expression (as a readout of mTOR activity) was reduced over the treatment period in the responding xenograft but expression increased to control (no treatment) levels on cessation of treatment. Phospho-AKT (Ser473) expression (as a readout of PI3K) was inhibited by both drugs but less markedly so than phospho-S6 expression. Initial tumor vol. redn. on treatment and regrowth rate after treatment cessation was assocd. with phospho-S6/total S6 expression ratio. Both drugs produced apoptosis but minimally influenced markers of proliferation (Ki67, phospho-histone H3). These results indicate that mTOR/PI3K inhibition can produce broad spectrum tumor growth stasis in ovarian cancer xenograft models during continuous chronic treatment and this is assocd. with apoptosis.
- 115Munster, P.; Aggarwal, R.; Hong, D.; Schellens, J. H.; van der Noll, R.; Specht, J.; Witteveen, P. O.; Werner, T. L.; Dees, E. C.; Bergsland, E.; Agarwal, N.; Kleha, J. F.; Durante, M.; Adams, L.; Smith, D. A.; Lampkin, T. A.; Morris, S. R.; Kurzrock, R. First-in-human phase I study of GSK2126458, an oral pan-class I Phosphatidylinositol-3-kinase inhibitor, in patients with advanced solid tumor malignancies. Clin. Cancer Res. 2016, 22, 1932– 1939, DOI: 10.1158/1078-0432.CCR-15-1665[Crossref], [PubMed], [CAS], Google Scholar115https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmsFeqsLs%253D&md5=3306a5e6586e8865bea5ef70aadf68d6First-in-Human Phase I Study of GSK2126458, an Oral Pan-Class I Phosphatidylinositol-3-Kinase Inhibitor, in Patients with Advanced Solid Tumor MalignanciesMunster, Pamela; Aggarwal, Rahul; Hong, David; Schellens, Jan H. M.; van der Noll, Ruud; Specht, Jennifer; Witteveen, Petronella O.; Werner, Theresa L.; Dees, E. Claire; Bergsland, Emily; Agarwal, Neeraj; Kleha, Joseph F.; Durante, Michael; Adams, Laurel; Smith, Deborah A.; Lampkin, Thomas A.; Morris, Shannon R.; Kurzrock, RazelleClinical Cancer Research (2016), 22 (8), 1932-1939CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)GSK2126458 (GSK458) is a potent inhibitor of PI3K (α, β, γ, and δ), with preclin. studies demonstrating broad antitumor activity. We performed a first-in-human phase I study in patients with advanced solid tumors. Patients received oral GSK458 once or twice daily in a dose-escalation design to define the max. tolerated dose (MTD). Expansion cohorts evaluated pharmacodynamics, pharmacokinetics, and clin. activity in histol. and molecularly defined cohorts. One hundred and seventy patients received doses ranging from 0.1 to 3 mg once or twice daily. Dose-limiting toxicities (grade 3 diarrhea, n = 4; fatigue and rash, n = 1) occurred in 5 patients (n = 3 at 3 mg/day). The MTD was 2.5 mg/day (MTD with twice daily dosing undefined). The most common grade ≥3 treatment-related adverse events included diarrhea (8%) and skin rash (5%). Pharmacokinetic analyses demonstrated increased duration of drug exposure above target level with twice daily dosing. Fasting insulin and glucose levels increased with dose and exposure of GSK458. Durable objective responses (ORs) were obsd. across multiple tumor types (sarcoma, kidney, breast, endometrial, oropharyngeal, and bladder cancer). Responses were not assocd. with PIK3CA mutations (OR rate: 5% wild-type vs. 6% mutant). Although the MTD of GSK458 was 2.5 mg once daily, twice-daily dosing may increase duration of target inhibition. Fasting insulin and glucose levels served as pharmacodynamic markers of drug exposure. Select patients achieved durable responses; however, PIK3CA mutations were neither necessary nor predictive of response. Combination treatment strategies and novel biomarkers may be needed to optimally target PI3K.
- 116Maher, T. M.; Bareille, P.; Costa, M. J.; Fahy, W. A.; Harrison, S. A.; Holman, B. F.; Lukey, P.; Mang, Y.; Saunders, P.; Simpson, J. K.; Toshner, R.; Woodcock, H. V.; Yang, S.; Marshall, R. P. A randomised, placebo-controlled, double-blind, repeat dose escalation study with omipalisib (GSK2126458) in patients with idiopathic pulmonary fibrosis (IPF). Am. J. Resp. Crit. Care 2017, 195, A7010
- 117Jere, S. W.; Houreld, N. N.; Abrahamse, H. Role of the PI3K/AKT (mTOR and GSK3β) signalling pathway and photobiomodulation in diabetic wound healing. Cytokine Growth Factor Rev. 2019, 50, 52– 59, DOI: 10.1016/j.cytogfr.2019.03.001[Crossref], [PubMed], [CAS], Google Scholar117https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXltFCrtb8%253D&md5=ae03796eef761c28bd5138c48c3ddd34Role of the PI3K/AKT (mTOR and GSK3β) signalling pathway and photobiomodulation in diabetic wound healingJere, Sandy W.; Houreld, Nicolette N.; Abrahamse, HeidiCytokine & Growth Factor Reviews (2019), 50 (), 52-59CODEN: CGFRFB; ISSN:1359-6101. (Elsevier Ltd.)A review. Activated phosphatidylinositol 3 kinase/Protein kinase B (PI3K/AKT) signalling with increased or reduced mTOR and GSK3β activity influences the wound repair process. Diabetic wounds, usually ulcerated, are characterised by reduced growth factors and cellular performance. The occurrence of diabetic ulcers is linked to peripheral arterial disease, neuropathy, and wound contamination. Lasers or light emitting diodes (LEDs) provide photon energy with therapeutic benefits (Photobiomodulation-PBM), and has been broadly commended to quicken diabetic wound healing. PBM is efficient in the visible red and near-IR electromagnetic spectrum, and fluencies ranging from 2 to 6 J/cm2. However, cellular and mol. mechanisms induced by PBM are not fully understood. In this review we discuss PBM and the PI3K/AKT pathway with specific focus on the mTOR and GSK3β downstream activity in diabetic wound healing.
- 118Villalobos-Labra, R.; Silva, L.; Subiabre, M.; Araos, J.; Salsoso, R.; Fuenzalida, B.; Sáez, T.; Toledo, F.; Gonzalez, M.; Quezada, C.; Pardo, F.; Chiarello, D. I.; Leiva, A.; Sobrevia, L. Akt/mTOR role in human foetoplacental vascular insulin resistance in diseases of pregnancy. J. Diabetes Res. 2017, 2017, 5947859, DOI: 10.1155/2017/5947859[Crossref], [PubMed], [CAS], Google Scholar118https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1M7nvFektQ%253D%253D&md5=13e3a2341fd41ae546c9f28cd7a6baa5Akt/mTOR Role in Human Foetoplacental Vascular Insulin Resistance in Diseases of PregnancyVillalobos-Labra Roberto; Silva Luis; Subiabre Mario; Araos Joaquin; Salsoso Rocio; Fuenzalida Barbara; Saez Tamara; Toledo Fernando; Pardo Fabian; Chiarello Delia I; Leiva Andrea; Sobrevia Luis; Silva Luis; Saez Tamara; Salsoso Rocio; Sobrevia Luis; Toledo Fernando; Gonzalez Marcelo; Quezada Claudia; Pardo Fabian; Sobrevia LuisJournal of diabetes research (2017), 2017 (), 5947859 ISSN:.Insulin resistance is characteristic of pregnancies where the mother shows metabolic alterations, such as preeclampsia (PE) and gestational diabetes mellitus (GDM), or abnormal maternal conditions such as pregestational maternal obesity (PGMO). Insulin signalling includes activation of insulin receptor substrates 1 and 2 (IRS1/2) as well as Src homology 2 domain-containing transforming protein 1, leading to activation of 44 and 42 kDa mitogen-activated protein kinases and protein kinase B/Akt (Akt) signalling cascades in the human foetoplacental vasculature. PE, GDM, and PGMO are abnormal conditions coursing with reduced insulin signalling, but the possibility of the involvement of similar cell signalling mechanisms is not addressed. This review aimed to determine whether reduced insulin signalling in PE, GDM, and PGMO shares a common mechanism in the human foetoplacental vasculature. Insulin resistance in these pathological conditions results from reduced Akt activation mainly due to inhibition of IRS1/2, likely due to the increased activity of the mammalian target of rapamycin (mTOR) resulting from lower activity of adenosine monophosphate kinase. Thus, a defective signalling via Akt/mTOR in response to insulin is a central and common mechanism of insulin resistance in these diseases of pregnancy. In this review, we summarise the cell signalling mechanisms behind the insulin resistance state in PE, GDM, and PGMO focused in the Akt/mTOR signalling pathway in the human foetoplacental endothelium.
- 119Kiyoi, H. Flt3 inhibitors: recent advances and problems for clinical application. Nagoya J. Med. Sci. 2015, 77, 7– 17[PubMed], [CAS], Google Scholar119https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhslalt7rL&md5=9a44962a3aa888bfdfd3fb49e388999aFLT3 inhibitors: recent advances and problems for clinical applicationKiyoi, HitoshiNagoya Journal of Medical Science (2015), 77 (1,2), 7-17CODEN: NJMSAG; ISSN:0027-7622. (Nagoya University School of Medicine, Graduate School of Medicine)FLT3, a type III receptor tyrosine kinase, expresses on most acute leukemia cells as well as normal hematopoietic stem/progenitor cells. Mutation in the FLT3 gene is the most frequent genetic alteration in acute myeloid leukemia (AML) and is well known as an important driver mutation for the development of myeloid malignancies. FLT3 mutation is a strong poor prognostic factor for the long-term survival in AML patients, while neither high-dose chemotherapy nor allogeneic hematopoietic stem cell transplantation can overcome a poor prognosis. Development of an FLT3 inhibitor is, therefore, much awaited. To date, several potent FLT3 inhibitors have been developed and some of them were evaluated for efficacy in clin. trials, although no FLT3 inhibitor has been yet approved. Moreover, several problems for clin. use, such as adverse effects, blood concn. and resistance have been apparent. Recently developed AC220 is a highly selective and sensitive FLT3 inhibitor. In Phase I and II trials, AC220 so far showed the best efficacy of AML cells harboring FLT3 mutation among clin. evaluated FLT3 inhibitors, while severe bone marrow suppression and QTc prolongation should be resolved for the clin. use. In this review, I summarize the characteristics of FLT3 inhibitors in clin. development and discuss important issues to be resolved for clin. use.
- 120Gucky, T.; Reznickova, E.; Radosova Muchova, T.; Jorda, R.; Klejova, Z.; Malinkova, V.; Berka, K.; Bazgier, V.; Ajani, H.; Lepsik, M.; Divoky, V.; Krystof, V. Discovery of N(2)-(4-amino-cyclohexyl)-9-cyclopentyl-N(6)-(4-morpholin-4-ylmethyl-phenyl)- 9H-purine-2,6-diamine as a potent FLT3 kinase inhibitor for Acute myeloid leukemia with FLT3 mutations. J. Med. Chem. 2018, 61, 3855– 3869, DOI: 10.1021/acs.jmedchem.7b01529[ACS Full Text], [CAS], Google Scholar120https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXotVahsr0%253D&md5=cbc982a08f1905840e273e23c825a134Discovery of N2-(4-Amino-cyclohexyl)-9-cyclopentyl-N6-(4-morpholin-4-ylmethyl-phenyl)-9H-purine-2,6-diamine as a Potent FLT3 Kinase Inhibitor for Acute Myeloid Leukemia with FLT3 MutationsGucky, Tomas; Reznickova, Eva; Radosova Muchova, Tereza; Jorda, Radek; Klejova, Zuzana; Malinkova, Veronika; Berka, Karel; Bazgier, Vaclav; Ajani, Haresh; Lepsik, Martin; Divoky, Vladimir; Krystof, VladimirJournal of Medicinal Chemistry (2018), 61 (9), 3855-3869CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)FLT3 tyrosine kinase is a potential drug target in acute myeloid leukemia (AML) because patients with FLT3-ITD mutations respond poorly to std. cytotoxic agents and there is a clear link between the disease and the oncogenic properties of FLT3. We present novel 2,6,9-trisubstituted purine derivs. with potent FLT3 inhibitory activity. The lead compd. 7d displays nanomolar activity in biochem. assays and selectively blocks proliferation of AML cell lines harboring FLT3-ITD mutations, whereas other transformed and normal human cells are several orders of magnitude less sensitive. The MV4-11 cells treated with 7d suppressed the phosphorylation of FLT3 and its downstream signaling pathways, with subsequent G1 cell cycle arrest and apoptosis. Addnl., a single dose of 7d in mice with s.c. MV4-11 xenografts caused sustained inhibition of FLT3 and STAT5 phosphorylation over 48 h, in contrast to the shorter effect obsd. after administration of the ref. FLT3 inhibitor quizartinib.
- 121Ramos, M. I.; Tak, P. P.; Lebre, M. C. Fms-like tyrosine kinase 3 ligand-dependent dendritic cells in autoimmune inflammation. Autoimmun. Rev. 2014, 13, 117– 124, DOI: 10.1016/j.autrev.2013.09.010[Crossref], [PubMed], [CAS], Google Scholar121https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1Oru7jK&md5=f1c59aa866bb34514d9f4f7c2864ab12Fms-like tyrosine kinase 3 ligand-dependent dendritic cells in autoimmune inflammationRamos, M. I.; Tak, P. P.; Lebre, M. C.Autoimmunity Reviews (2014), 13 (2), 117-124CODEN: ARUEBU; ISSN:1568-9972. (Elsevier B.V.)A review. Dendritic cells (DCs) are specialized in capture, processing and presentation of antigens to T cells. Depending on the type of DC and its activation state, the interaction of DCs with naive T cells can lead to different types of immune response, or to T-cell tolerance. The existence of many specialized subtypes of DCs with particular functions has raised the need to distinguish DCs formed in steady-state from those produced during an inflammatory response. In patients with autoimmune disease and in exptl. animal models of autoimmunity, DCs show abnormalities in both nos. and activation state, expressing immunogenic levels of co-stimulatory mols. and pro-inflammatory cytokines. Initial in vitro studies of cytokines in DC development revealed distinct and important roles for the receptor tyrosine kinases, granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF, also called CSF1) and fms-like tyrosine kinase 3 ligand (Flt3L) in the generation of DCs. Flt3L is crit. for instructing DC generation throughout different organs and regulates DC development from Flt3+ lymphoid and myeloid-committed progenitors to DCs in vivo. The aim of this review is to provide an overview of the role of Flt3L-dependent DCs in the immunopathogenesis of autoimmunity and chronic inflammation and its potential as therapeutic targets.
- 122Kazi, J. U.; Ronnstrand, L. Fms-like tyrosine kinase 3/FLT3: from basic science to clinical implications. Physiol. Rev. 2019, 99, 1433– 1466, DOI: 10.1152/physrev.00029.2018[Crossref], [PubMed], [CAS], Google Scholar122https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFGlurrE&md5=ed99d5ecf4de02acb8196801e4e66e6aFMS-like tyrosine kinase 3/FLT3: from basic science to clinical implicationsKazi, Julhash U.; Roennstrand, LarsPhysiological Reviews (2019), 99 (3), 1433-1466CODEN: PHREA7; ISSN:1522-1210. (American Physiological Society)A review. FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase that is expressed almost exclusively in the hematopoietic compartment. Its ligand, FLT3 ligand (FL), induces dimerization and activation of its intrinsic tyrosine kinase activity. Activation of FLT3 leads to its autophosphorylation and initiation of several signal transduction cascades. Signaling is initiated by the recruitment of signal transduction mols. to activated FLT3 through binding to specific phosphorylated tyrosine residues in the intracellular region of FLT3. Activation of FLT3 mediates cell survival, cell proliferation, and differentiation of hematopoietic progenitor cells. It acts in synergy with several other cytokines to promote its biol. effects. Deregulated FLT3 activity has been implicated in several diseases, most prominently in acute myeloid leukemia where around one-third of patients carry an activating mutant of FLT3 which drives the disease and is correlated with poor prognosis. Overactivity of FLT3 has also been implicated in autoimmune diseases, such as rheumatoid arthritis. The observation that gain-of-function mutations of FLT3 can promote leukemogenesis has stimulated the development of inhibitors that target this receptor. Many of these are in clin. trials, and some have been approved for clin. use. However, problems with acquired resistance to these inhibitors are common and, furthermore, only a fraction of patients respond to these selective treatments. This review provides a summary of our current knowledge regarding structural and functional aspects of FLT3 signaling, both under normal and pathol. conditions, and discusses challenges for the future regarding the use of targeted inhibition of these pathways for the treatment of patients.
- 123Rivat, C.; Sar, C.; Mechaly, I.; Leyris, J. P.; Diouloufet, L.; Sonrier, C.; Philipson, Y.; Lucas, O.; Mallie, S.; Jouvenel, A.; Tassou, A.; Haton, H.; Venteo, S.; Pin, J. P.; Trinquet, E.; Charrier-Savournin, F.; Mezghrani, A.; Joly, W.; Mion, J.; Schmitt, M.; Pattyn, A.; Marmigere, F.; Sokoloff, P.; Carroll, P.; Rognan, D.; Valmier, J. Inhibition of neuronal FLT3 receptor tyrosine kinase alleviates peripheral neuropathic pain in mice. Nat. Commun. 2018, 9, 1042, DOI: 10.1038/s41467-018-03496-2[Crossref], [PubMed], [CAS], Google Scholar123https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1Mngtlegsg%253D%253D&md5=b07de24bfa7b2fb2e3f2c2cfe63bb9b2Inhibition of neuronal FLT3 receptor tyrosine kinase alleviates peripheral neuropathic pain in miceRivat Cyril; Sar Chamroeun; Mechaly Ilana; Leyris Jean-Philippe; Diouloufet Lucie; Sonrier Corinne; Lucas Olivier; Mallie Sylvie; Jouvenel Antoine; Tassou Adrien; Haton Henri; Venteo Stephanie; Mezghrani Alexandre; Joly Willy; Mion Julie; Pattyn Alexandre; Marmigere Frederic; Carroll Patrick; Valmier Jean; Rivat Cyril; Sar Chamroeun; Mechaly Ilana; Mallie Sylvie; Jouvenel Antoine; Tassou Adrien; Haton Henri; Valmier Jean; Leyris Jean-Philippe; Sonrier Corinne; Sokoloff Pierre; Philipson Yann; Schmitt Martine; Rognan Didier; Pin Jean-Philippe; Trinquet Eric; Charrier-Savournin FabienneNature communications (2018), 9 (1), 1042 ISSN:.Peripheral neuropathic pain (PNP) is a debilitating and intractable chronic disease, for which sensitization of somatosensory neurons present in dorsal root ganglia that project to the dorsal spinal cord is a key physiopathological process. Here, we show that hematopoietic cells present at the nerve injury site express the cytokine FL, the ligand of fms-like tyrosine kinase 3 receptor (FLT3). FLT3 activation by intra-sciatic nerve injection of FL is sufficient to produce pain hypersensitivity, activate PNP-associated gene expression and generate short-term and long-term sensitization of sensory neurons. Nerve injury-induced PNP symptoms and associated-molecular changes were strongly altered in Flt3-deficient mice or reversed after neuronal FLT3 downregulation in wild-type mice. A first-in-class FLT3 negative allosteric modulator, discovered by structure-based in silico screening, strongly reduced nerve injury-induced sensory hypersensitivity, but had no effect on nociception in non-injured animals. Collectively, our data suggest a new and specific therapeutic approach for PNP.
- 124Stone, R. M.; Manley, P. W.; Larson, R. A.; Capdeville, R. Midostaurin: its odyssey from discovery to approval for treating acute myeloid leukemia and advanced systemic mastocytosis. Blood Adv. 2018, 2, 444– 453, DOI: 10.1182/bloodadvances.2017011080[Crossref], [PubMed], [CAS], Google Scholar124https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXlsFOqtLs%253D&md5=2ce639598ecadae547e507f116704247Midostaurin: its odyssey from discovery to approval for treating acute myeloid leukemia and advanced systemic mastocytosisStone, Richard M.; Manley, Paul W.; Larson, Richard A.; Capdeville, RenaudBlood Advances (2018), 2 (4), 444-453CODEN: BALDBA; ISSN:2473-9537. (American Society of Hematology)A review. Midostaurin was a prototype kinase inhibitor, originally developed as a protein kinase C inhibitor and subsequently as an angiogenesis inhibitor, based on its inhibition of vascular endothelial growth factor receptor. Despite promising preclin. data, early clin. trials in multiple diseases showed only modest efficacy. In 1996, the relatively frequent occurrence of fms-like tyrosine kinase 3 (FLT3) activating mutations in acute myeloid leukemia (AML) was first recognized. Several years later, midostaurin was discovered to be a potent inhibitor of the FLT3 tyrosine kinase and to have activity against mutant forms of KIT proto-oncogene receptor tyrosine kinase, which drive advanced systemic mastocytosis (SM). Through a series of collaborations between industry and academia, midostaurin in combination with std. chemotherapy was evaluated in the Cancer and Leukemia Group B 10603/RATIFY study, a large, phase 3, randomized, placebo-controlled trial in patients with newly diagnosed FLT3-mutated AML. This was the first study to show significant improvements in overall survival and event-free survival with the addn. of a targeted therapy to std. chemotherapy in this population. Around the same time, durable responses were also obsd. in other trials of midostaurin in patients with advanced SM. Collectively, these clin. data led to the approval of midostaurin by the US Food and Drug Administration and the European Medicines Agency for both newly diagnosed FLT3-mutated AML and advanced SM.
- 125Gotlib, J.; Kluin-Nelemans, H. C.; George, T. I.; Akin, C.; Sotlar, K.; Hermine, O.; Awan, F. T.; Hexner, E.; Mauro, M. J.; Sternberg, D. W.; Villeneuve, M.; Huntsman Labed, A.; Stanek, E. J.; Hartmann, K.; Horny, H. P.; Valent, P.; Reiter, A. Efficacy and safety of midostaurin in advanced systemic mastocytosis. N. Engl. J. Med. 2016, 374, 2530– 2541, DOI: 10.1056/NEJMoa1513098[Crossref], [PubMed], [CAS], Google Scholar125https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvF2ksrvI&md5=c3b12f782bf5eec9fe84085d3809784bEfficacy and safety of midostaurin in advanced systemic mastocytosisGotlib, Jason; Kluin-Nelemans, Hanneke C.; George, Tracy I.; Akin, Cem; Sotlar, Karl; Hermine, Olivier; Awan, Farrukh T.; Hexner, Elizabeth; Mauro, Michael J.; Sternberg, David W.; Villeneuve, Matthieu; Labed, Alice Huntsman; Stanek, Eric J.; Hartmann, Karin; Horny, Hans-Peter; Valent, Peter; Reiter, AndreasNew England Journal of Medicine (2016), 374 (26), 2530-2541CODEN: NEJMAG; ISSN:1533-4406. (Massachusetts Medical Society)BACKGROUND: Advanced systemic mastocytosis comprises rare hematol. neoplasms that are assocd. with a poor prognosis and lack effective treatment options. The multikinase inhibitor midostaurin inhibits KIT D816V, a primary driver of disease pathogenesis. METHODS: We conducted an open-label study of oral midostaurin at a dose of 100 mg twice daily in 116 patients, of whom 89 with mastocytosis-related organ damage were eligible for inclusion in the primary efficacy population; 16 had aggressive systemic mastocytosis, 57 had systemic mastocytosis with an assocd. hematol. neoplasm, and 16 had mast-cell leukemia. The primary outcome was the best overall response. RESULTS: The overall response rate was 60% (95% confidence interval [CI], 49 to 70); 45% of the patients had a major response, which was defined as complete resoln. of at least one type of mastocytosis-related organ damage. Response rates were similar regardless of the subtype of advanced systemic mastocytosis, KIT mutation status, or exposure to previous therapy. The median best percentage changes in bone marrow mast-cell burden and serum tryptase level were -59% and -58%, resp. The median overall survival was 28.7 mo, and the median progression-free survival was 14.1 mo. Among the 16 patients with mast-cell leukemia, the median overall survival was 9.4 mo (95% CI, 7.5 to not estd.). Dose redn. owing to toxic effects occurred in 56% of the patients; re-escalation to the starting dose was feasible in 32% of those patients. The most frequent adverse events were low-grade nausea, vomiting, and diarrhea. New or worsening grade 3 or 4 neutropenia, anemia, and thrombocytopenia occurred in 24%, 41%, and 29% of the patients, resp., mostly in those with preexisting cytopenias. CONCLUSIONS: In this open-label study, midostaurin showed efficacy in patients with advanced systemic mastocytosis, including the highly fatal variant mast-cell leukemia.
- 126Campochiaro, P. A. Reduction of diabetic macular edema by oral administration of the kinase inhibitor PKC412. Invest. Ophthalmol. Visual Sci. 2004, 45, 922– 931, DOI: 10.1167/iovs.03-0955[Crossref], [PubMed], [CAS], Google Scholar126https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2c%252FpsFGrtw%253D%253D&md5=473379b2c21d18961353d37d9f0f54cbReduction of diabetic macular edema by oral administration of the kinase inhibitor PKC412Campochiaro Peter AInvestigative ophthalmology & visual science (2004), 45 (3), 922-31 ISSN:0146-0404.PURPOSE: To evaluate the efficacy and safety of PKC412, an orally administered kinase inhibitor, in subjects with diabetic macular edema. METHODS: This was a randomized (1:1:1:1), multicenter, double-masked, parallel-group study in which subjects (n = 141) received placebo or PKC412 (50, 100, or 150 mg/d) for up to 3 months. Subjects were 18 to 85 years of age and had retinal thickening that met predefined criteria and best corrected visual acuity of 55 letters or more. Efficacy was based on changes in retinal thickening measured by grading of fundus photographs and optical coherence tomography (OCT) and changes in visual acuity. RESULTS: Grading of fundus photographs showed a statistically significant decrease in the area of greatest retinal thickening in patients receiving 150 mg/d of PKC412 (P = 0.032). OCT demonstrated that the two higher doses of PKC412 caused a significant decrease in thickening in the region of greatest thickening and in the fovea (P < or = 039), with response in the high-dose group significantly different from that in the placebo group (difference = -66.69 micro m [95.2% CI: -128.57 to -4.81]; P = 0.030). Retinal volume for all locations also showed a significant decrease from baseline in the 100- and 150-mg/d PKC412 groups (P < or = 004), and the 150-mg/kg group showed significantly less retinal volume than the placebo group at 3 months (difference = -0.46 mm(3) [95.2% CI: -0.86-0.06]; P = 0.019). There was a small (4.36 letters), but significant (P = 0.007), improvement in visual acuity at 3 months compared with baseline in the 100-mg/d PKC412 group. Gastrointestinal side effects (diarrhea, nausea, and vomiting) were the most common adverse events attributed to the drug. Dose-related effects were observed for tolerability, glycemic control, and liver toxicity. CONCLUSIONS: Orally administered PKC412 at doses of 100 mg/d or higher may significantly reduce macular edema and improve visual acuity in diabetic subjects. However, concern regarding liver toxicity with systemic therapy makes local delivery an appealing approach.
- 127William, A. D.; Lee, A. C.; Poulsen, A.; Goh, K. C.; Madan, B.; Hart, S.; Tan, E.; Wang, H.; Nagaraj, H.; Chen, D.; Lee, C. P.; Sun, E. T.; Jayaraman, R.; Pasha, M. K.; Ethirajulu, K.; Wood, J. M.; Dymock, B. W. Discovery of the macrocycle (9E)-15-(2-(pyrrolidin-1-yl)ethoxy)-7,12,25-trioxa-19,21,24-triaza-tetracyclo[18. 3.1.1(2,5).1(14,18)]hexacosa-1(24),2,4,9,14(26),15,17,20,22-nonaene (SB1578), a potent inhibitor of janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) for the treatment of rheumatoid arthritis. J. Med. Chem. 2012, 55, 2623– 2640, DOI: 10.1021/jm201454n[ACS Full Text], [CAS], Google Scholar127https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XisFShsLY%253D&md5=efe684c2f2ff0b506d02c2ef911bfb2fDiscovery of the Macrocycle (9E)-15-(2-(Pyrrolidin-1-yl)ethoxy)-7,12,25-trioxa-19,21,24-triaza-tetracyclo[18.3.1.1(2,5).1(14,18)]hexacosa-1(24),2,4,9,14(26),15,17,20,22-nonaene (SB1578), a Potent Inhibitor of Janus Kinase 2/Fms-LikeTyrosine Kinase-3 (JAK2/FLT3) for the Treatment of Rheumatoid ArthritisWilliam, Anthony D.; Lee, Angeline C.-H.; Poulsen, Anders; Goh, Kee Chuan; Madan, Babita; Hart, Stefan; Tan, Evelyn; Wang, Haishan; Nagaraj, Harish; Chen, Dizhong; Lee, Chai Ping; Sun, Eric T.; Jayaraman, Ramesh; Pasha, Mohammad Khalid; Ethirajulu, Kantharaj; Wood, Jeanette M.; Dymock, Brian W.Journal of Medicinal Chemistry (2012), 55 (6), 2623-2640CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Herein, we describe the synthesis and SAR of a series of small mol. macrocycles that selectively inhibit JAK2 kinase within the JAK family and FLT3 kinase. Following a multiparameter optimization of a key aryl ring of the previously described SB1518 (pacritinib), the highly sol. 14l (I) was selected as the optimal compd. Oral efficacy in the murine collagen-induced arthritis (CIA) model for rheumatoid arthritis (RA) supported 14l as a potential treatment for autoimmune diseases and inflammatory disorders such as psoriasis and RA. Compd. 14l (SB1578) was progressed into development and is currently undergoing phase 1 clin. trials in healthy volunteers.
- 128Li, G. B.; Ma, S.; Yang, L. L.; Ji, S.; Fang, Z.; Zhang, G.; Wang, L. J.; Zhong, J. M.; Xiong, Y.; Wang, J. H.; Huang, S. Z.; Li, L. L.; Xiang, R.; Niu, D.; Chen, Y. C.; Yang, S. Y. Drug discovery against psoriasis: identification of a new potent Fms-like tyrosine kinase 3 (FLT3) inhibitor, 1-(4-((1H-pyrazolo[3,4-d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-3-(5-(tert-butyl)iso xazol-3-yl)urea, that showed potent activity in a psoriatic animal model. J. Med. Chem. 2016, 59, 8293– 8305, DOI: 10.1021/acs.jmedchem.6b00604[ACS Full Text], [CAS], Google Scholar128https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlOgt73L&md5=82b107175f8c3b7a2e1fc3e5db6d488eDrug Discovery against Psoriasis: Identification of a New Potent FMS-like Tyrosine Kinase 3 (FLT3) Inhibitor, 1-(4-((1H-Pyrazolo[3,4-d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-3-(5-(tert-butyl)isoxazol-3-yl)urea, That Showed Potent Activity in a Psoriatic Animal ModelLi, Guo-Bo; Ma, Shuang; Yang, Ling-Ling; Ji, Sen; Fang, Zhen; Zhang, Guo; Wang, Li-Jiao; Zhong, Jie-Min; Xiong, Yu; Wang, Jiang-Hong; Huang, Shen-Zhen; Li, Lin-Li; Xiang, Rong; Niu, Dawen; Chen, Ying-Chun; Yang, Sheng-YongJournal of Medicinal Chemistry (2016), 59 (18), 8293-8305CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Psoriasis is a chronic T-cell-mediated autoimmune disease, and FMS-like tyrosine kinase 3 (FLT3) has been considered as a potential mol. target for the treatment of psoriasis. In this investigation, structural optimization was performed on a lead compd., 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)phenyl)-3-(4-chloro-3- (trifluoromethyl)phenyl)urea, which showed a moderate inhibitory activity against FLT3. A series of pyrazolo[3,4-d]pyrimidine derivs. were synthesized, and structure-activity relationship anal. led to the discovery of a no. of potent FLT3 inhibitors. One of the most active compds., 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(5-tert-butylisoxazol-3-yl)urea (I), was then chosen for in-depth anti-psoriasis studies because this compd. displayed the highest potency in a preliminary anti-psoriasis test. Compd. I exhibited significant anti-psoriatic effects in the K14-VEGF transgenic mouse model of psoriasis, and no recurrence was found 15 days later after the last administration. Detailed mechanisms of action of compd. I were also investigated. Collectively, compd. I could be a potential drug candidate for psoriasis treatment.
- 129Yang, L. L.; Li, G. B.; Ma, S.; Zou, C.; Zhou, S.; Sun, Q. Z.; Cheng, C.; Chen, X.; Wang, L. J.; Feng, S.; Li, L. L.; Yang, S. Y. Structure-activity relationship studies of pyrazolo[3,4-d]pyrimidine derivatives leading to the discovery of a novel multikinase inhibitor that potently inhibits FLT3 and VEGFR2 and evaluation of its activity against acute myeloid leukemia in vitro and in vivo. J. Med. Chem. 2013, 56, 1641– 1655, DOI: 10.1021/jm301537p[ACS Full Text], [CAS], Google Scholar129https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvVCjtbs%253D&md5=49142fb4b7dfa62310b090ed073b490fStructure-Activity Relationship Studies of Pyrazolo[3,4-d]pyrimidine Derivatives Leading to the Discovery of a Novel Multikinase Inhibitor That Potently Inhibits FLT3 and VEGFR2 and Evaluation of Its Activity against Acute Myeloid Leukemia in Vitro and in VivoYang, Ling-Ling; Li, Guo-Bo; Ma, Shuang; Zou, Chan; Zhou, Shu; Sun, Qi-Zheng; Cheng, Chuan; Chen, Xin; Wang, Li-Jiao; Feng, Shan; Li, Lin-Li; Yang, Sheng-YongJournal of Medicinal Chemistry (2013), 56 (4), 1641-1655CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Pyrazolopyrimidinyloxyphenyl ureas such as I were prepd. as inhibitors of the kinases Flt3 and VEGFR2 for potential use as antitumor agents. Structural modification of an initial pyrazolopyrimidinyloxyphenyl urea lead compd. and detn. of the relationships of Flt3 inhibition, inhibition of proliferation, and inhibition of angiogenesis in human acute myeloid leukemia (AML) cells and in transgenic-zebrafish to the structure of pyrazolopyrimidinyloxyphenyl ureas led to the discovery of I. I was a multikinase inhibitor that potently inhibited both FLT3 (IC50 = 39 nM) and VEGFR2 (IC50 = 12 nM). In an AML xenograft mouse model, a once-daily dose of I at 10 mg/kg for 18 days led to complete tumor regression without obvious toxicity; the mechanism of action of I was studied.
- 130Yan, H. X.; Li, W. W.; Zhang, Y.; Wei, X. W.; Fu, L. X.; Shen, G. B.; Yin, T.; Li, X. Y.; Shi, H. S.; Wan, Y.; Zhang, Q. Y.; Li, J.; Yang, S. Y.; Wei, Y. Q. Accumulation of FLT3(+) CD11c (+) dendritic cells in psoriatic lesions and the anti-psoriatic effect of a selective FLT3 inhibitor. Immunol. Res. 2014, 60, 112– 126, DOI: 10.1007/s12026-014-8521-4[Crossref], [PubMed], [CAS], Google Scholar130https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXpsFelt7g%253D&md5=cccc42ce83e27f8d222d9f3087481a1aAccumulation of FLT3+ CD11c+ dendritic cells in psoriatic lesions and the anti-psoriatic effect of a selective FLT3 inhibitorYan, Heng-Xiu; Li, Wei-Wei; Zhang, Yan; Wei, Xia-Wei; Fu, Li-Xin; Shen, Guo-Bo; Yin, Tao; Li, Xiu-Ying; Shi, Hua-Shan; Wan, Yang; Zhang, Qing-Yin; Li, Jiong; Yang, Sheng-Yong; Wei, Yu-QuanImmunologic Research (2014), 60 (1), 112-126CODEN: IMRSEB; ISSN:0257-277X. (Springer)Psoriasis is a common chronic T-cell-mediated autoimmune skin disease, and traditional immunotherapies for psoriasis have focused on the direct inhibition of T cells, which often causes toxicity and lacks long-term effectiveness. Safe and effective therapeutic strategies are strongly needed for psoriasis. In this study, we show for the first time a significant accumulation of FLT3+ CD11c+ dendritic cells (DCs) in human psoriatic lesions and in the skin of exptl. preclin. K14-VEGF transgenic homozygous mice, our animal model, although not an exact match for human psoriasis, displays many characteristics of inflammatory skin inflammation. SKLB4771, a potent and selective FLT3 inhibitor that we designed and synthesized, was used to treat cutaneous inflammation and psoriasis-like symptoms of disease in mice and almost completely cured the psoriasis-like disease without obvious toxicity. Mechanistic studies indicated that SKLB4771 treatment significantly decreased the no. and activation of pDCs and mDCs in vitro and in vivo, and subsequent T-cell cascade reactions mediated by Th1/Th17 pathways. These findings show that targeted inhibition of FLT3, and hence direct interference with DCs, may be a novel therapeutic approach for the treatment of psoriasis.
- 131Ichijo, H.; Nishida, E.; Irie, K.; Ten Dijke, P.; Saitoh, M.; Moriguchi, T.; Takagi, M.; Matsumoto, K.; Miyazono, K.; Gotoh, Y. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science 1997, 275, 90– 94, DOI: 10.1126/science.275.5296.90[Crossref], [PubMed], [CAS], Google Scholar131https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXjsFSmtQ%253D%253D&md5=c848d137cce82c79a75a21efb217feaeInduction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathwaysIchijo, Hidenori; Nishida, Eisuke; Irie, Kenji; ten Dijke, Peter; Saitoh, Masao; Moriguchi, Tetsuo; Takagi, Minoru; Matsumoto, Kunihiro; Miyazono, Kohei; Gotoh, YukihoScience (Washington, D. C.) (1997), 275 (5296), 90-94CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Mitogen-activated protein (MAP) kinase cascades are activated in response to various extracellular stimuli, including growth factors and environmental stresses. A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, resp. Overexpression of ASK1 induced apoptotic cell death, and ASK1 was activated in cells treated with tumor necrosis factor-α (TNF-α). Moreover, TNF-α-induced apoptosis was inhibited by a catalytically inactive form of ASK1. ASK1 may be a key element in the mechanism of stress- and cytokine-induced apoptosis.
- 132Baig, M. H.; Baker, A.; Ashraf, G. M.; Dong, J. J. ASK1 and its role in cardiovascular and other disorders: available treatments and future prospects. Expert Rev. Proteomics 2019, 16, 857– 870, DOI: 10.1080/14789450.2019.1676735[Crossref], [PubMed], [CAS], Google Scholar132https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFyhtbbO&md5=cd18d7b2840b4f7c16611e94e93d1984ASK1 and its role in cardiovascular and other disorders: available treatments and future prospectsBaig, Mohammad Hassan; Baker, Abu; Ashraf, Ghulam M.; Dong, Jae-JuneExpert Review of Proteomics (2019), 16 (10), 857-870CODEN: ERPXA3; ISSN:1478-9450. (Taylor & Francis Ltd.)A review. Apoptosis signal-regulating kinase 1 (ASK1), also known as MAP3K5, is a member of mitogen-activated protein kinase kinase kinase (MAP3K) family and is well reported as crucial in the regulation of the JNK and P38 pathways. ASK1 is activated in response to a diverse array of stresses such as endoplasmic reticulum stress, lipopolysaccharides, tumor necrosis factor alpha, and reactive oxygen species. The activation of ASK1 induces various stress responses.: Considering ASK1 as an important therapeutic drug target, here we have discussed the role of ASK1 in the progression of various diseases. We have also provided an overview of the available inhibitors for ASK1. The success of computational-based approaches toward ASK1 inhibitor design has also been discussed.: A no. of reports have outlined the prominent role of ASK1 in the pathogenesis of several diseases. The discovery of novel ASK1 inhibitors would have a wide range of applications in medical science. In-silico techniques have been successfully used in the design of some novel ASK1 inhibitors. The use of machine learning-based approaches in combination with structure-based virtual screening (SBVS) and ligand-based virtual screening (LBVS) will be helpful toward the development of potent ASK1 inhibitors.
- 133Fujisawa, T. Therapeutic application of apoptosis signal-regulating kinase 1 inhibitors. Adv. Biol. Regul 2017, 66, 85– 90, DOI: 10.1016/j.jbior.2017.10.004[Crossref], [PubMed], [CAS], Google Scholar133https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs12rur7N&md5=91ed7baecfcf9fb42c0437fa8ebbf87aTherapeutic application of apoptosis signal-regulating kinase 1 inhibitorsFujisawa, TakaoAdvances in Biological Regulation (2017), 66 (), 85-90CODEN: ABRDE5; ISSN:2212-4934. (Elsevier Ltd.)A review. Apoptosis signal-regulating kinase 1 (ASK1) is a member of the stress-activated mitogen-activated protein kinase kinase kinase (MAP3K) family. ASK1 is an attractive drug target, owing to its essential role in a wide variety of human diseases including neurodegenerative disorders, inflammatory diseases and cancer. Recent studies have suggested that pharmacol. manipulations using small mol. ASK1 inhibitors may be beneficial in exptl. human disease models. In this review, we highlight the current understanding of ASK1 inhibitors as a potential therapy for human diseases.
- 134Kawarazaki, Y.; Ichijo, H.; Naguro, I. Apoptosis signal-regulating kinase 1 as a therapeutic target. Expert Opin. Ther. Targets 2014, 18, 651– 664, DOI: 10.1517/14728222.2014.896903[Crossref], [PubMed], [CAS], Google Scholar134https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXotlWgsr8%253D&md5=85423452f6b9e36c4b62986b5c086081Apoptosis signal-regulating kinase 1 as a therapeutic targetKawarazaki, Yosuke; Ichijo, Hidenori; Naguro, IsaoExpert Opinion on Therapeutic Targets (2014), 18 (6), 651-664CODEN: EOTTAO; ISSN:1472-8222. (Informa Healthcare)A review. Introduction: All organisms are ordinarily exposed to various stresses. It is important for organisms to possess appropriate stress response mechanisms and to maintain homeostasis because the disruption of a stress response system can cause various diseases. Apoptosis signal-regulating kinase 1 (ASK1) is one of the stress-responsive MAP3Ks. ASK1 plays an important role in the response to reactive oxygen species (ROS), endoplasmic reticulum stress and pro-inflammatory cytokines, and it is involved in the pathogenesis of various diseases. Areas covered: In this review, the authors describe recent literature concerning the intricate and elaborate regulation system of ASK1, the function of ASK1 during a cellular stress response and the involvement of ASK1 in many diseases, including cancer, neurodegenerative diseases, infections, diabetes and cardiovascular diseases. Expert opinion: In certain disease conditions, ASK1 plays a protective role, whereas ASK1 can exacerbate the pathol. of other diseases. Although ASK1 is involved in various diseases, there is no therapy or drug that targets ASK1 for use in a clin. setting. Recently, ASK1 inhibitors (K811 and MSC2032964A) have emerged, and their therapeutic potentials have been tested in vivo. ASK1 is currently receiving considerable attention as a new therapeutic target.
- 135Loomba, R.; Lawitz, E.; Mantry, P. S.; Jayakumar, S.; Caldwell, S. H.; Arnold, H.; Diehl, A. M.; Djedjos, C. S.; Han, L.; Myers, R. P.; Subramanian, G. M.; McHutchison, J. G.; Goodman, Z. D.; Afdhal, N. H.; Charlton, M. R. Investigators, GS-US-384–1497. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial. Hepatology 2018, 67, 549– 559, DOI: 10.1002/hep.29514[Crossref], [PubMed], [CAS], Google Scholar135https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsFKjtbs%253D&md5=ca04f9bbc0b7d65c2b4493d479c2d751The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trialLoomba, Rohit; Lawitz, Eric; Mantry, Parvez S.; Jayakumar, Saumya; Caldwell, Stephen H.; Arnold, Hays; Diehl, Anna Mae; Djedjos, C. Stephen; Han, Ling; Myers, Robert P.; Subramanian, G. Mani; McHutchison, John G.; Goodman, Zachary D.; Afdhal, Nezam H.; Charlton, Michael R.Hepatology (Hoboken, NJ, United States) (2018), 67 (2), 549-559CODEN: HPTLD9; ISSN:0270-9139. (John Wiley & Sons, Inc.)Inhibition of apoptosis signal-regulating kinase 1, a serine/threonine kinase, leads to improvement in inflammation and fibrosis in animal models of nonalcoholic steatohepatitis. We evaluated the safety and efficacy of selonsertib, a selective inhibitor of apoptosis signal-regulating kinase 1, alone or in combination with simtuzumab, in patients with nonalcoholic steatohepatitis and stage 2 or 3 liver fibrosis. In this multicenter phase 2 trial, 72 patients were randomized to receive 24 wk of open-label treatment with either 6 or 18 mg of selonsertib orally once daily with or without once-weekly injections of 125 mg of simtuzumab or simtuzumab alone. The effect of treatment was assessed by paired pretreatment and posttreatment liver biopsies, magnetic resonance elastog., magnetic resonance imaging-estd. proton d. fat fraction, quant. collagen content, and noninvasive markers of liver injury. Due to the lack of effect of simtuzumab on histol. or selonsertib pharmacokinetics, selonsertib groups with and without simtuzumab were pooled. After 24 wk of treatment, the proportion of patients with a one or more stage redn. in fibrosis in the 18-mg selonsertib group was 13 of 30 (43%; 95% confidence interval, 26-63); in the 6-mg selonsertib group, 8 of 27 (30%; 95% confidence interval, 14-50); and in the simtuzumab-alone group, 2 of 10 (20%; 95% confidence interval, 3-56). Improvement in fibrosis was assocd. with redns. in liver stiffness on magnetic resonance elastog., collagen content and lobular inflammation on liver biopsy, as well as improvements in serum biomarkers of apoptosis and necrosis. There were no significant differences in adverse events between the treatment groups. Conclusion: These findings suggest that selonsertib may reduce liver fibrosis in patients with nonalcoholic steatohepatitis and stage 2-3 fibrosis. (Hepatol. 2018;67:549-559).
- 136Harrison, S. A.; Wong, V. W.; Okanoue, T.; Bzowej, N.; Vuppalanchi, R.; Younes, Z.; Kohli, A.; Sarin, S.; Caldwell, S. H.; Alkhouri, N.; Shiffman, M. L.; Camargo, M.; Li, G.; Kersey, K.; Jia, C.; Zhu, Y.; Djedjos, C. S.; Subramanian, G. M.; Myers, R. P.; Gunn, N.; Sheikh, A.; Anstee, Q. M.; Romero-Gomez, M.; Trauner, M.; Goodman, Z.; Lawitz, E. J.; Younossi, Z. Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: Results from randomized phase III STELLAR trials. J. Hepatol. 2020, 73, 26– 39, DOI: 10.1016/j.jhep.2020.02.027[Crossref], [PubMed], [CAS], Google Scholar136https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXlvFGks7o%253D&md5=a7b9e9142c45ab137a849b7b3a8e6c38Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: Results from randomized phase III STELLAR trialsHarrison, Stephen A.; Wong, Vincent Wai-Sun; Okanoue, Takeshi; Bzowej, Natalie; Vuppalanchi, Raj; Younes, Ziad; Kohli, Anita; Sarin, Shiv; Caldwell, Stephen H.; Alkhouri, Naim; Shiffman, Mitchell L.; Camargo, Marianne; Li, Georgia; Kersey, Kathryn; Jia, Catherine; Zhu, Yanni; Djedjos, C. Stephen; Subramanian, G. Mani; Myers, Robert P.; Gunn, Nadege; Sheikh, Aasim; Anstee, Quentin M.; Romero-Gomez, Manuel; Trauner, Michael; Goodman, Zachary; Lawitz, Eric J.; Younossi, ZobairJournal of Hepatology (2020), 73 (1), 26-39CODEN: JOHEEC; ISSN:0168-8278. (Elsevier B.V.)Apoptosis signal-regulating kinase 1 (ASK1) plays a key role in hepatocyte injury, inflammation, and fibrosis in non-alc. steatohepatitis (NASH). We evaluated the safety and antifibrotic effect of selonsertib, a selective inhibitor of ASK1, in patients with advanced fibrosis due to NASH.We conducted 2 randomized, double-blind, placebo-controlled, phase III trials of selonsertib in patients with NASH and bridging fibrosis (F3, STELLAR-3) or compensated cirrhosis (F4, STELLAR-4). Patients were randomized 2:2:1 to receive selonsertib 18 mg, selonsertib 6 mg, or placebo once daily for 48 wk. Liver biopsies were performed at screening and week 48 and non-invasive tests of fibrosis (NITs) were evaluated. The primary efficacy endpoint was the proportion of patients with ≥1-stage improvement in fibrosis without worsening of NASH at week 48. Addnl. endpoints included changes in NITs, progression to cirrhosis (in STELLAR-3), and liver-related clin. events.Neither trial met the primary efficacy endpoint. In STELLAR-3, fibrosis improvement without worsening of NASH was obsd. in 10% (31/322, p = 0.49 vs. placebo), 12% (39/321, p = 0.93 vs. placebo), and 13% (21/159) of patients in the selonsertib 18 mg, selonsertib 6 mg, and placebo groups, resp. In STELLAR-4, the primary endpoint was achieved in 14% (51/354; p = 0.56), 13% (45/351; p = 0.93), and 13% (22/172) of patients, resp. Although selonsertib led to dose-dependent redns. in hepatic phospho-p38 expression indicative of pharmacodynamic activity, it had no significant effect on liver biochem., NITs, progression to cirrhosis, or adjudicated clin. events. The rates and types of adverse events were similar among selonsertib and placebo groups.Forty-eight weeks of selonsertib monotherapy had no antifibrotic effect in patients with bridging fibrosis or compensated cirrhosis due to NASH.Patients with non-alc. steatohepatitis (NASH) can develop scarring of the liver (fibrosis), including cirrhosis, which increases the risks of liver failure and liver cancer. We tested whether 48 wk of treatment with selonsertib reduced fibrosis in patients with NASH and advanced liver scarring. We did not find that selonsertib reduced fibrosis in these patients.Clinicaltrials.gov nos. NCT03053050 and NCT03053063.
- 137Chertow, G. M.; Pergola, P. E.; Chen, F.; Kirby, B. J.; Sundy, J. S.; Patel, U. D. Effects of selonsertib in patients with diabetic kidney disease. J. Am. Soc. Nephrol. 2019, 30, 1980– 1990, DOI: 10.1681/ASN.2018121231[Crossref], [PubMed], [CAS], Google Scholar137https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXnsFGqu78%253D&md5=3387b2e69941bfac54796a36528e1f4cEffects of selonsertib in patients with diabetic kidney diseaseChertow, Glenn M.; Pergola, Pablo E.; Chen, Fang; Kirby, Brian J.; Sundy, John S.; Pate, Uptal D.Journal of the American Society of Nephrology (2019), 30 (10), 1980-1990CODEN: JASNEU; ISSN:1046-6673. (American Society of Nephrology)Background Apoptosis signal-regulating kinase 1 (ASK1) activation in glomerular and tubular cells result- ing from oxidative stress may drive kidney disease progression. Findings in animal models identified selonsertib, a selective ASK1 inhibitor, as a potential therapeutic agent. Methods In a phase 2 trial evaluating selonsertib's safety and efficacy in adults with type 2 diabetes and treatment-refractory moderate-to-advanced diabetic kidney disease, we randomly assigned 333 adults in a 1:1:1:1 allocation to selonsertib (oral daily doses of 2, 6, or 18 mg) or placebo. Primary outcome was change from baseline eGFR at 48 wk. Results Selonsertib appeared safe, with no dose-dependent adverse effects over 48 wk. Although mean eGFR for selonsertib and placebo groups did not differ significantly at 48 wk, acute effects related to inhibition of creatinine secretion by selonsertib confounded eGFR differences at 48 wk. Because of this unanticipated effect, we used piecewise linear regression, finding two dose-dependent effects: an acute and more pronounced eGFR decline from 0 to 4 wk (creatinine secretion effect) and an attenuated eGFR decline between 4 and 48 wk (therapeutic effect) with higher doses of selonsertib. A post hoc anal. (excluding data for 20 patients from two sites with Good Clin. Practice compliance- related issues) found that between 4 and 48 wk, rate of eGFR decline was reduced 71% for the 18-mg group relative to placebo (difference 3.11±1.53 mL/min per 1.73 m2 annualized over 1 yr; 95% confi- dence interval, 0.10-6.13; nominal P=0.043). Effects on urine albumin-to-creatinine ratio did not differ between selonsertib and placebo. Conclusions Although the trial did not meet its primary endpoint, exploratory post hoc analyses suggest that selonsertib may slow diabetic kidney disease progression.
- 138Anstee, Q. M.; Lawitz, E. J.; Alkhouri, N.; Wong, V. W.; Romero-Gomez, M.; Okanoue, T.; Trauner, M.; Kersey, K.; Li, G.; Han, L.; Jia, C.; Wang, L.; Chen, G.; Subramanian, G. M.; Myers, R. P.; Djedjos, C. S.; Kohli, A.; Bzowej, N.; Younes, Z.; Sarin, S.; Shiffman, M. L.; Harrison, S. A.; Afdhal, N. H.; Goodman, Z.; Younossi, Z. M. Noninvasive tests accurately identify advanced fibrosis due to NASH: baseline data from the STELLAR trials. Hepatology 2019, 70, 1521– 1530, DOI: 10.1002/hep.30842[Crossref], [PubMed], [CAS], Google Scholar138https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3MzjvFOlsw%253D%253D&md5=81adfb1725cdaa92816f9e43155d9a17Noninvasive Tests Accurately Identify Advanced Fibrosis due to NASH: Baseline Data From the STELLAR TrialsAnstee Quentin M; Anstee Quentin M; Lawitz Eric J; Alkhouri Naim; Wong Vincent Wai-Sun; Romero-Gomez Manuel; Okanoue Takeshi; Trauner Michael; Kersey Kathryn; Li Georgia; Han Ling; Jia Catherine; Wang Lulu; Chen Guang; Subramanian G Mani; Myers Robert P; Djedjos C Stephen; Kohli Anita; Bzowej Natalie; Younes Ziad; Sarin Shiv; Shiffman Mitchell L; Harrison Stephen A; Afdhal Nezam H; Goodman Zachary; Younossi Zobair MHepatology (Baltimore, Md.) (2019), 70 (5), 1521-1530 ISSN:.Accurate noninvasive tests (NITs) are needed to replace liver biopsy for identifying advanced fibrosis caused by nonalcoholic steatohepatitis (NASH). We analyzed screening data from two phase 3 trials of selonsertib to assess the ability of NITs to discriminate advanced fibrosis. Centrally read biopsies from the STELLAR studies, which enrolled patients with bridging fibrosis and compensated cirrhosis, were staged according to the NASH Clinical Research Network classification. We explored associations between fibrosis stage and NITs, including the nonalcoholic fatty liver disease fibrosis score (NFS), fibrosis-4 (FIB-4) index, Enhanced Liver Fibrosis (ELF) test, and liver stiffness by vibration-controlled transient elastography (LS by VCTE). The performance of these tests to discriminate advanced fibrosis, either alone or in combinations, was evaluated using areas under the receiver operating characteristic curve (AUROCs) with 5-fold cross-validation repeated 100 times. Of the 4,404 patients screened for these trials, 3,202 had evaluable biopsy data: 940 with F0-F2 fibrosis and 2,262 with F3-F4 fibrosis. Significant differences between median values of NITs for patients with F0-F2 versus F3-F4 fibrosis were observed: -0.972 versus 0.318 for NFS, 1.18 versus 2.20 for FIB-4, 9.22 versus 10.39 for ELF, and 8.8 versus 16.5 kPa for LS by VCTE (all P < 0.001). AUROCs ranged from 0.75 to 0.80 to discriminate advanced fibrosis. FIB-4 followed by an LS by VCTE or ELF test in those with indeterminate values (FIB-4 between 1.3 and 2.67) maintained an acceptable performance while reducing the rate of indeterminate results. Conclusion: Among patients being considered for enrollment into clinical trials, NITs alone or in combination can reduce the need for liver biopsy to discriminate advanced fibrosis caused by NASH. The predictive value of these tests for general screening will require confirmation in a real-world population.
- 139Lanier, M.; Pickens, J.; Bigi, S. V.; Bradshaw-Pierce, E. L.; Chambers, A.; Cheruvallath, Z. S.; Cole, D.; Dougan, D. R.; Ermolieff, J.; Gibson, T.; Halkowycz, P.; Hirokawa, A.; Ivetac, A.; McBride, C.; Miura, J.; Nunez, E.; Sabat, M.; Tyhonas, J.; Wang, H. X.; Wang, X. L.; Swann, S. Structure-based design of ASK1 inhibitors as potential agents for heart failure. ACS Med. Chem. Lett. 2017, 8, 1341– 1341, DOI: 10.1021/acsmedchemlett.7b00457[ACS Full Text], [CAS], Google Scholar139https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslOmsL%252FP&md5=ba3724601624b9af4ffa26ab9b266f35Correction to "Structure-Based Design of ASK1 Inhibitors as Potential Agents for Heart Failure" [Erratum to document cited in CA166:413694]Lanier, Marion; Pickens, Jason; Bigi, Simone V.; Bradshaw-Pierce, Erica L.; Chambers, Alison; Cheruvallath, Zacharia S.; Cole, Derek; Dougan, Douglas R.; Ermolieff, Jacques; Gibson, Tony; Halkowycz, Petro; Hirokawa, Aki; Ivetac, Anthony; Miura, Joanne; Nunez, Evan; Sabat, Mark; Tyhonas, John; Wang, Haixia; Wang, Xiaolun; Swann, SteveACS Medicinal Chemistry Letters (2017), 8 (12), 1341CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)In the original publication, author Chris McBride was omitted from the author list; the correction is provided here.
- 140Himmelbauer, M. K.; Xin, Z. L.; Jones, J. H.; Enyedy, I.; King, K.; Marcotte, D. J.; Murugan, P.; Santoro, J. C.; Hesson, T.; Spilker, K.; Johnson, J. L.; Luzzio, M. J.; Gilfillan, R.; de Turiso, F. G. L. Rational design and optimization of a novel class of macrocyclic apoptosis signal-regulating kinase 1 inhibitors. J. Med. Chem. 2019, 62, 10740– 10756, DOI: 10.1021/acs.jmedchem.9b01206[ACS Full Text], [CAS], Google Scholar140https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitFeqsrnL&md5=bceb203a92c314a775b1d8d116cafcadRational Design and Optimization of a Novel Class of Macrocyclic Apoptosis Signal-Regulating Kinase 1 InhibitorsHimmelbauer, Martin K.; Xin, Zhili; Jones, J. Howard; Enyedy, Istvan; King, Kristopher; Marcotte, Douglas J.; Murugan, Paramasivam; Santoro, Joseph C.; Hesson, Thomas; Spilker, Kerri; Johnson, Joshua L.; Luzzio, Michael J.; Gilfillan, Rab; de Turiso, Felix Gonzalez-LopezJournal of Medicinal Chemistry (2019), 62 (23), 10740-10756CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Structural anal. of a known ASK1 inhibitor bound to its kinase domain led to the design and synthesis of the novel macrocyclic inhibitor I (cell IC50 = 1.2μM). The profile of this compd. was optimized for CNS penetration following two independent strategies: a rational design approach leading to II and a parallel synthesis approach leading to III. Both analogs are potent ASK1 inhibitors in biochem. and cellular assays (II, cell IC50 = 95 nM; III, cell IC50 = 123 nM) and have moderate to low efflux ratio (ER) in an MDR1-MDCK assay (II, ER = 5.2; III, ER = 1.5). In vivo PK studies revealed that inhibitor II had moderate CNS penetration (Kp,uu = 0.17) and analog III had high CNS penetration (Kp,uu = 1.0).
- 141Guo, X.; Harada, C.; Namekata, K.; Matsuzawa, A.; Camps, M.; Ji, H.; Swinnen, D.; Jorand-Lebrun, C.; Muzerelle, M.; Vitte, P. A.; Ruckle, T.; Kimura, A.; Kohyama, K.; Matsumoto, Y.; Ichijo, H.; Harada, T. Regulation of the severity of neuroinflammation and demyelination by TLR-ASK1-p38 pathway. EMBO Mol. Med. 2010, 2, 504– 515, DOI: 10.1002/emmm.201000103[Crossref], [PubMed], [CAS], Google Scholar141https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXosFeiuw%253D%253D&md5=f164a951b512af060b05b2906cbad96eRegulation of the severity of neuroinflammation and demyelination by TLR-ASK1-p38 pathwayGuo, Xiaoli; Harada, Chikako; Namekata, Kazuhiko; Matsuzawa, Atsushi; Camps, Monsterrat; Ji, Hong; Swinnen, Dominique; Jorand-Lebrun, Catherine; Muzerelle, Mathilde; Vitte, Pierre-Alain; Ruckle, Thomas; Kimura, Atsuko; Kohyama, Kuniko; Matsumoto, Yoh; Ichijo, Hidenori; Harada, TakayukiEMBO Molecular Medicine (2010), 2 (12), 504-515CODEN: EMMMAM; ISSN:1757-4684. (Wiley-Blackwell)Apoptosis signal-regulating kinase 1 (ASK1) is an evolutionarily conserved mitogen-activated protein kinase (MAPK) kinase kinase which plays important roles in stress and immune responses. Here, we show that ASK1 deficiency attenuates neuroinflammation in exptl. autoimmune encephalomyelitis (EAE), without affecting the proliferation capability of T cells. Moreover, we found that EAE upregulates expression of Toll-like receptors (TLRs) in activated astrocytes and microglia, and that TLRs can synergize with ASK1-p38 MAPK signalling in the release of key chemokines from astrocytes. Consequently, oral treatment with a specific small mol. wt. inhibitor of ASK1 suppressed EAE-induced autoimmune inflammation in both spinal cords and optic nerves. These results suggest that the TLR-ASK1-p38 pathway in glial cells may serve as a valid therapeutic target for autoimmune demyelinating disorders including multiple sclerosis.
- 142Fujisawa, T.; Takahashi, M.; Tsukamoto, Y.; Yamaguchi, N.; Nakoji, M.; Endo, M.; Kodaira, H.; Hayashi, Y.; Nishitoh, H.; Naguro, I.; Homma, K.; Ichijo, H. The ASK1-specific inhibitors K811 and K812 prolong survival in a mouse model of amyotrophic lateral sclerosis. Hum. Mol. Genet. 2016, 25, 245– 253, DOI: 10.1093/hmg/ddv467[Crossref], [PubMed], [CAS], Google Scholar142https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtF2ltbvP&md5=cfa4702fbeed701f7e2640e3cb7931deThe ASK1-specific inhibitors K811 and K812 prolong survival in a mouse model of amyotrophic lateral sclerosisFujisawa, Takao; Takahashi, Motoo; Tsukamoto, Yuka; Yamaguchi, Namiko; Nakoji, Masayoshi; Endo, Megumi; Kodaira, Hiroshi; Hayashi, Yuki; Nishitoh, Hideki; Naguro, Isao; Homma, Kengo; Ichijo, HidenoriHuman Molecular Genetics (2016), 25 (2), 245-253CODEN: HMGEE5; ISSN:0964-6906. (Oxford University Press)Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no cure. To develop effective treatments for this devastating disease, an appropriate strategy for targeting the mol. responsible for the pathogenesis of ALS is needed. We previously reported that mutant SOD1 protein causes motor neuron death through activation of ASK1, a mitogen-activated protein kinase kinase kinase. Addnl., we recently developed K811 (I) and K812 (II), which are selective inhibitors for ASK1. Here, we report the effect of K811 and K812 in a mouse model of ALS (SOD1G93A transgenic mice). Oral administration of K811 or K812 significantly extended the life span of SOD1G93A transgenic mice (1.06 and 1.08% improvement in survival). Moreover, ASK1 activation obsd. in the lumbar spinal cord of mice at the disease progression stage was markedly decreased in the K811- and K812-treated groups. In parallel, immunohistochem. anal. revealed that K811 and K812 treatment inhibited glial activation in the lumbar spinal cord of SOD1G93A transgenic mice. These results reinforce the importance of ASK1 as a therapeutic target for ALS treatment.
- 143Budas, G. R.; Boehm, M.; Kojonazarov, B.; Viswanathan, G.; Tian, X.; Veeroju, S.; Novoyatleva, T.; Grimminger, F.; Hinojosa-Kirschenbaum, F.; Ghofrani, H. A.; Weissmann, N.; Seeger, W.; Liles, J. T.; Schermuly, R. T. Ask1 inhibition halts disease progression in preclinical models of pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 2018, 197, 373– 385, DOI: 10.1164/rccm.201703-0502OC[Crossref], [PubMed], [CAS], Google Scholar143https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitFKks77N&md5=7a4d24e0cff8fb71b778c66cb954a7abASK1 inhibition halts disease progression in preclinical models of pulmonary arterial hypertensionBudas, Grant R.; Boehm, Mario; Kojonazarov, Baktybek; Viswanathan, Gayathri; Tian, Xia; Veeroju, Swathi; Novoyatleva, Tatyana; Grimminger, Friedrich; Hinojosa-Kirschenbaum, Ford; Ghofrani, Hossein A.; Weissmann, Norbert; Seeger, Werner; Liles, John T.; Schermuly, Ralph T.American Journal of Respiratory and Critical Care Medicine (2018), 197 (3), 373-385CODEN: AJCMED; ISSN:1073-449X. (American Thoracic Society)Rationale: Progression of pulmonary arterial hypertension (PAH) is assocd. with pathol. remodeling of the pulmonary vasculature and the right ventricle (RV). Oxidative stress drives the remodeling process through activation of MAPKs (mitogen-activated protein kinases), which stimulate apoptosis, inflammation, and fibrosis. Objectives: We investigated whether pharmacol. inhibition of the redox-sensitive apical MAPK, ASK1 (apoptosis signal-regulating kinase 1), can halt the progression of pulmonary vascular and RV remodeling. Methods: A selective, orally available ASK1 inhibitor, GS-444217, was administered to two preclin. rat models of PAH (monocrotaline and Sugen/hypoxia), a murine model of RV pressure overload induced by pulmonary artery banding, and cellular models. Measurements and Main Results: Oral administration of GS- 444217 dose dependently reduced pulmonary arterial pressure and reduced RV hypertrophy in PAH models. The therapeutic efficacy of GS-444217 was assocd. with reduced ASK1 phosphorylation, reduced muscularization of the pulmonary arteries, and reduced fibrotic gene expression in the RV. Importantly, efficacy was obsd. when GS-444217 was administered to animals with established disease and also directly reduced cardiac fibrosis and improved cardiac function in a model of isolated RV pressure overload. In cellular models, GS-444217 reduced phosphorylation of p38 and JNK (c-Jun N-terminal kinase) induced by adenoviral overexpression of ASK1 in rat cardiomyocytes and reduced activation/migration of primary mouse cardiac fibroblasts and human pulmonary adventitial fibroblasts derived from patients with PAH. Conclusions: ASK1 inhibition reduced pathol. remodeling of the pulmonary vasculature and the right ventricle and halted progression of pulmonary hypertension in rodent models. These preclin. data inform the first description of a causal role of ASK1 in PAH disease pathogenesis.
- 144Zhang, D.; Lin, J.; Han, J. Receptor-interacting protein (RIP) kinase family. Cell. Mol. Immunol. 2010, 7, 243– 249, DOI: 10.1038/cmi.2010.10[Crossref], [PubMed], [CAS], Google Scholar144https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXotlSms7w%253D&md5=e110b4cbd223b7ddef4855830c7d4156Receptor-interacting protein (RIP) kinase familyZhang, Duanwu; Lin, Juan; Han, JiahuaiCellular & Molecular Immunology (2010), 7 (4), 243-249CODEN: CMIEAO; ISSN:1672-7681. (NPG Nature Asia-Pacific)A review. Receptor-interacting protein (RIP) kinases are a group of threonine/serine protein kinases with a relatively conserved kinase domain but distinct non-kinase regions. A no. of different domain structures, such as death and caspase activation and recruitment domain (CARD) domains, were found in different RIP family members, and these domains should be keys in detg. the specific function of each RIP kinase. It is known that RIP kinases participate in different biol. processes, including those in innate immunity, but their downstream substrates are largely unknown. This review will give an overview of the structures and functions of RIP family members, and an update of recent progress in RIP kinase research.
- 145Declercq, W.; Vanden Berghe, T.; Vandenabeele, P. RIP kinases at the crossroads of cell death and survival. Cell 2009, 138, 229– 232, DOI: 10.1016/j.cell.2009.07.006[Crossref], [PubMed], [CAS], Google Scholar145https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtVSgtrzK&md5=5f75989020b487729d5c9112b246d9c5RIP kinases at the crossroads of cell death and survivalDeclercq, Wim; Vanden Berghe, Tom; Vandenabeele, PeterCell (Cambridge, MA, United States) (2009), 138 (2), 229-232CODEN: CELLB5; ISSN:0092-8674. (Cell Press)A review. Protein kinases of the receptor interacting protein (RIP) family collaborate with death receptor proteins to regulate cell death. Recent studies reveal that RIP3 kinase functions with RIP1 at the crossroads of apoptosis, necroptosis, and cell survival.
- 146Cuny, G. D.; Degterev, A. RIPK protein kinase family: Atypical lives of typical kinases. Semin. Cell Dev. Biol. 2020, DOI: 10.1016/j.semcdb.2020.06.014 .
- 147Martens, S.; Hofmans, S.; Declercq, W.; Augustyns, K.; Vandenabeele, P. Inhibitors targeting RIPK1/RIPK3: old and new drugs. Trends Pharmacol. Sci. 2020, 41, 209– 224, DOI: 10.1016/j.tips.2020.01.002[Crossref], [PubMed], [CAS], Google Scholar147https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhvFShsLc%253D&md5=fa5bbc5b08590333606d3de18f1dd61aInhibitors Targeting RIPK1/RIPK3: Old and New DrugsMartens, Sofie; Hofmans, Sam; Declercq, Wim; Augustyns, Koen; Vandenabeele, PeterTrends in Pharmacological Sciences (2020), 41 (3), 209-224CODEN: TPHSDY; ISSN:0165-6147. (Elsevier Ltd.)A review. The scaffolding function of receptor-interacting protein kinase 1 (RIPK1) regulates prosurvival signaling and inflammatory gene expression, while its kinase activity mediates both apoptosis and necroptosis; the latter involving RIPK3 kinase activity. The mutual transition between the scaffold and kinase functions of RIPK1 is regulated by (de)ubiquitylation and (de)phosphorylation. RIPK1-mediated cell death leads to disruption of epithelial barriers and/or release of damage-assocd. mol. patterns (DAMPs), cytokines, and chemokines, propagating inflammatory and degenerative diseases. Many drug development programs have pursued targeting RIPK1, and to a lesser extent RIPK3 kinase activity. In this review, we classify existing and novel small-mol. drugs based on their pharmacodynamic (PD) type I, II, and III binding mode. Finally, we discuss their applicability and therapeutic potential in inflammatory and degenerative exptl. disease models.
- 148Xu, J.; Wei, Q.; He, Z. Insight into the function of RIPK4 in keratinocyte differentiation and carcinogenesis. Front. Oncol. 2020, 10, 1562, DOI: 10.3389/fonc.2020.01562[Crossref], [PubMed], [CAS], Google Scholar148https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB38bot1aiug%253D%253D&md5=d253fdeea567ef4e2cb6b23c624cd31fInsight Into the Function of RIPK4 in Keratinocyte Differentiation and CarcinogenesisXu Jing; Wei Qichun; He ZhixingFrontiers in oncology (2020), 10 (), 1562 ISSN:2234-943X.The receptor-interacting protein kinase 4 (RIPK4), a member of the RIPK family, was originally described as an interaction partner of protein kinase C (PKC) β and PKCδ. RIPK4 is identified as a key regulator of keratinocyte differentiation, cutaneous inflammation, and cutaneous wound repair. The mechanism by which RIPK4 integrates upstream signals to initiate specific responses remains elusive. Previous studies have indicated that RIPK4 can regulate several signaling pathways, including the NF-κB, Wnt/β-catenin, and RAF/MEK/ERK pathways. Furthermore, RIPK4-related biological signaling pathways interact with each other to form a complex network. Mounting evidence suggests that RIPK4 is aberrantly expressed in various kinds of cancers. In several types of squamous cell carcinoma (SCC), the mutations that drive aggressive SCC have been found in RIPK4. In addition, the function of RIPK4 in carcinogenesis is probably tissue-specific, since RIPK4 can play a dual role as both a tumor promoter and a tumor suppressor in different tumor types. Therefore, RIPK4 may represent as an independent prognostic factor and a promising novel therapeutic target, which can be used to identify the risks of patients and guide personalized treatments. In future, RIPK4-interacting pathways and precise molecular targets need to be investigated in order to further elucidate the mechanisms underlying epidermal differentiation and carcinogenesis.
- 149Wegner, K. W.; Saleh, D.; Degterev, A. Complex pathologic roles of RIPK1 and RIPK3: moving beyond necroptosis. Trends Pharmacol. Sci. 2017, 38, 202– 225, DOI: 10.1016/j.tips.2016.12.005[Crossref], [PubMed], [CAS], Google Scholar149https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXlt12ltA%253D%253D&md5=296e25764f643a458906f2a9aac1df05Complex Pathologic Roles of RIPK1 and RIPK3: Moving Beyond NecroptosisWegner, Kelby W.; Saleh, Danish; Degterev, AlexeiTrends in Pharmacological Sciences (2017), 38 (3), 202-225CODEN: TPHSDY; ISSN:0165-6147. (Elsevier Ltd.)A review. A process of regulated necrosis, termed necroptosis, has been recognized as a major contributor to cell death and inflammation occurring under a wide range of pathol. settings. The core event in necroptosis is the formation of the detergent-insol. 'necrosome' complex of homologous Ser/Thr kinases, receptor protein interacting kinase 1 (RIPK1) and receptor interacting protein kinase 3 (RIPK3), which promotes phosphorylation of a key prodeath effector, mixed lineage kinase domain-like (MLKL), by RIPK3. Core necroptosis mediators are under multiple controls, which have been a subject of intense investigation. Addnl., non-necroptotic functions of these factors, primarily in controlling apoptosis and inflammatory responses, have also begun to emerge. This review will provide an overview of the current understanding of the human disease relevance of this pathway, and potential therapeutic strategies, targeting necroptosis mediators in various pathologies.
- 150Harris, P. A.; Berger, S. B.; Jeong, J. U.; Nagilla, R.; Bandyopadhyay, D.; Campobasso, N.; Capriotti, C. A.; Cox, J. A.; Dare, L.; Dong, X.; Eidam, P. M.; Finger, J. N.; Hoffman, S. J.; Kang, J.; Kasparcova, V.; King, B. W.; Lehr, R.; Lan, Y.; Leister, L. K.; Lich, J. D.; MacDonald, T. T.; Miller, N. A.; Ouellette, M. T.; Pao, C. S.; Rahman, A.; Reilly, M. A.; Rendina, A. R.; Rivera, E. J.; Schaeffer, M. C.; Sehon, C. A.; Singhaus, R. R.; Sun, H. H.; Swift, B. A.; Totoritis, R. D.; Vossenkamper, A.; Ward, P.; Wisnoski, D. D.; Zhang, D.; Marquis, R. W.; Gough, P. J.; Bertin, J. Discovery of a first-in-class Receptor interacting protein 1 (RIP1) kinase specific clinical candidate (GSK2982772) for the treatment of inflammatory diseases. J. Med. Chem. 2017, 60, 1247– 1261, DOI: 10.1021/acs.jmedchem.6b01751[ACS Full Text], [CAS], Google Scholar150https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXitVeksLk%253D&md5=ee0c3c60bb1351dff696490ac9edb1ccDiscovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory DiseasesHarris, Philip A.; Berger, Scott B.; Jeong, Jae U.; Nagilla, Rakesh; Bandyopadhyay, Deepak; Campobasso, Nino; Capriotti, Carol A.; Cox, Julie A.; Dare, Lauren; Dong, Xiaoyang; Eidam, Patrick M.; Finger, Joshua N.; Hoffman, Sandra J.; Kang, James; Kasparcova, Viera; King, Bryan W.; Lehr, Ruth; Lan, Yunfeng; Leister, Lara K.; Lich, John D.; MacDonald, Thomas T.; Miller, Nathan A.; Ouellette, Michael T.; Pao, Christina S.; Rahman, Attiq; Reilly, Michael A.; Rendina, Alan R.; Rivera, Elizabeth J.; Schaeffer, Michelle C.; Sehon, Clark A.; Singhaus, Robert R.; Sun, Helen H.; Swift, Barbara A.; Totoritis, Rachel D.; Vossenkamper, Anna; Ward, Paris; Wisnoski, David D.; Zhang, Daohua; Marquis, Robert W.; Gough, Peter J.; Bertin, JohnJournal of Medicinal Chemistry (2017), 60 (4), 1247-1261CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)RIP1 regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-mol. inhibitors of RIP1 kinase that are suitable for advancement into the clinic have yet to be described. Herein, the authors report the lead optimization of a benzoxazepinone hit from a DNA-encoded library and the discovery and profile of clin. candidate GSK2982772 (compd. I), currently in phase 2a clin. studies for psoriasis, rheumatoid arthritis, and ulcerative colitis. Compd. I potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking many TNF-dependent cellular responses. Highlighting its potential as a novel anti-inflammatory agent, the inhibitor was also able to reduce spontaneous prodn. of cytokines from human ulcerative colitis explants. The highly favorable physicochem. and ADMET properties of I, combined with high potency, led to a predicted low oral dose in humans.
- 151Yoshikawa, M.; Saitoh, M.; Katoh, T.; Seki, T.; Bigi, S. V.; Shimizu, Y.; Ishii, T.; Okai, T.; Kuno, M.; Hattori, H.; Watanabe, E.; Saikatendu, K. S.; Zou, H.; Nakakariya, M.; Tatamiya, T.; Nakada, Y.; Yogo, T. Discovery of 7-oxo-2,4,5,7-tetrahydro-6 H-pyrazolo[3,4- c]pyridine derivatives as potent, orally available, and brain-penetrating Receptor interacting protein 1 (RIP1) kinase inhibitors: analysis of structure-kinetic relationships. J. Med. Chem. 2018, 61, 2384– 2409, DOI: 10.1021/acs.jmedchem.7b01647[ACS Full Text], [CAS], Google Scholar151https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjtlOku78%253D&md5=a76ab7f12af03e277ba37d7ea08274c9Discovery of 7-Oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine Derivatives as Potent, Orally Available, and Brain-Penetrating Receptor Interacting Protein 1 (RIP1) Kinase Inhibitors: Analysis of Structure-Kinetic RelationshipsYoshikawa, Masato; Saitoh, Morihisa; Katoh, Taisuke; Seki, Tomohiro; Bigi, Simone V.; Shimizu, Yuji; Ishii, Tsuyoshi; Okai, Takuro; Kuno, Masako; Hattori, Harumi; Watanabe, Etsuro; Saikatendu, Kumar S.; Zou, Hua; Nakakariya, Masanori; Tatamiya, Takayuki; Nakada, Yoshihisa; Yogo, TakatoshiJournal of Medicinal Chemistry (2018), 61 (6), 2384-2409CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The authors report the discovery of 7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine derivs. as a novel class of receptor interacting protein 1 (RIP1) kinase inhibitors. On the basis of the overlay study between HTS hit 10 and GSK2982772 in RIP1 kinase, the authors designed and synthesized a novel class of RIP1 kinase inhibitor (11, (3S)-3-(2-Benzyl-4-oxo-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-5-methyl-2,3-dihydro-1,5-benzoxazepin-4(5H)-one trifluoroacetic acid) possessing moderate RIP1 kinase inhibitory activity and P-gp mediated efflux. The optimization of the core structure and the exploration of appropriate substituents utilizing SBDD approach led to the discovery of (22, (3S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-8-carbonitrile), a highly potent, orally available, and brain-penetrating RIP1 kinase inhibitor with excellent PK profiles. Compd. 22 significantly suppressed necroptotic cell death both in mouse and human cells. Oral administration of 22 (10 mg/kg, bid) attenuated disease progression in the mouse exptl. autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Moreover, anal. of structure-kinetic relationship (SKR) for the authors' novel chem. series was also discussed.
- 152Patel, S.; Webster, J. D.; Varfolomeev, E.; Kwon, Y. C.; Cheng, J. H.; Zhang, J.; Dugger, D. L.; Wickliffe, K. E.; Maltzman, A.; Sujatha-Bhaskar, S.; Bir Kohli, P.; Ramaswamy, S.; Deshmukh, G.; Liederer, B. M.; Fong, R.; Hamilton, G.; Lupardus, P.; Caplazi, P.; Lee, W. P.; van Lookeren Campagne, M.; Johnson, A.; McKenzie, B. S.; Junttila, M. R.; Newton, K.; Vucic, D. RIP1 inhibition blocks inflammatory diseases but not tumor growth or metastases. Cell Death Differ. 2020, 27, 161– 175, DOI: 10.1038/s41418-019-0347-0[Crossref], [PubMed], [CAS], Google Scholar152https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFSmsbjO&md5=d3639164630df8f3dc21403367aef1c6RIP1 inhibition blocks inflammatory diseases but not tumor growth or metastasisPatel, Snahel; Webster, Joshua D.; Varfolomeev, Eugene; Kwon, Youngsu C.; Cheng, Jason H.; Zhang, Juan; Dugger, Debra L.; Wickliffe, Kate E.; Maltzman, Allie; Sujatha-Bhaskar, Swathi; Bir Kohli, Pawan; Ramaswamy, Sreema; Deshmukh, Gauri; Liederer, Bianca M.; Fong, Rina; Hamilton, Greg; Lupardus, Patrick; Caplazi, Patrick; Lee, Wyne P.; van Lookeren Campagne, Menno; Johnson, Adam; McKenzie, Brent S.; Junttila, Melissa R.; Newton, Kim; Vucic, DomagojCell Death & Differentiation (2020), 27 (1), 161-175CODEN: CDDIEK; ISSN:1350-9047. (Nature Research)The kinase RIP1 acts in multiple signaling pathways to regulate inflammatory responses and it can trigger both apoptosis and necroptosis. Its kinase activity has been implicated in a range of inflammatory, neurodegenerative, and oncogenic diseases. Here, we explore the effect of inhibiting RIP1 genetically, using knock-in mice that express catalytically inactive RIP1 D138N, or pharmacol., using the murine-potent inhibitor GNE684. Inhibition of RIP1 reduced collagen antibody-induced arthritis, and prevented skin inflammation caused by mutation of Sharpin, or colitis caused by deletion of Nemo from intestinal epithelial cells. Conversely, inhibition of RIP1 had no effect on tumor growth or survival in pancreatic tumor models driven by mutant Kras, nor did it reduce lung metastases in a B16 melanoma model. Collectively, our data emphasize a role for the kinase activity of RIP1 in certain inflammatory disease models, but question its relevance to tumor progression and metastasis.
- 153Harris, P. A.; Faucher, N.; George, N.; Eidam, P. M.; King, B. W.; White, G. V.; Anderson, N. A.; Bandyopadhyay, D.; Beal, A. M.; Beneton, V.; Berger, S. B.; Campobasso, N.; Campos, S.; Capriotti, C. A.; Cox, J. A.; Daugan, A.; Donche, F.; Fouchet, M. H.; Finger, J. N.; Geddes, B.; Gough, P. J.; Grondin, P.; Hoffman, B. L.; Hoffman, S. J.; Hutchinson, S. E.; Jeong, J. U.; Jigorel, E.; Lamoureux, P.; Leister, L. K.; Lich, J. D.; Mahajan, M. K.; Meslamani, J.; Mosley, J. E.; Nagilla, R.; Nassau, P. M.; Ng, S. L.; Ouellette, M. T.; Pasikanti, K. K.; Potvain, F.; Reilly, M. A.; Rivera, E. J.; Sautet, S.; Schaeffer, M. C.; Sehon, C. A.; Sun, H.; Thorpe, J. H.; Totoritis, R. D.; Ward, P.; Wellaway, N.; Wisnoski, D. D.; Woolven, J. M.; Bertin, J.; Marquis, R. W. Discovery and lead-optimization of 4,5-dihydropyrazoles as mono-kinase selective, orally bioavailable and efficacious inhibitors of Receptor interacting protein 1 (RIP1) kinase. J. Med. Chem. 2019, 62, 5096– 5110, DOI: 10.1021/acs.jmedchem.9b00318[ACS Full Text], [CAS], Google Scholar153https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXot1Sgsb8%253D&md5=eb3cdf239442f7364f51a79a56d43cbdDiscovery and Lead-Optimization of 4,5-Dihydropyrazoles as Mono-Kinase Selective, Orally Bioavailable and Efficacious Inhibitors of Receptor Interacting Protein 1 (RIP1) KinaseHarris, Philip A.; Faucher, Nicolas; George, Nicolas; Eidam, Patrick M.; King, Bryan W.; White, Gemma V.; Anderson, Niall A.; Bandyopadhyay, Deepak; Beal, Allison M.; Beneton, Veronique; Berger, Scott B.; Campobasso, Nino; Campos, Sebastien; Capriotti, Carol A.; Cox, Julie A.; Daugan, Alain; Donche, Frederic; Fouchet, Marie-Helene; Finger, Joshua N.; Geddes, Brad; Gough, Peter J.; Grondin, Pascal; Hoffman, Bonnie L.; Hoffman, Sandra J.; Hutchinson, Susan E.; Jeong, Jae U.; Jigorel, Emilie; Lamoureux, Pauline; Leister, Lara K.; Lich, John D.; Mahajan, Mukesh K.; Meslamani, Jamel; Mosley, Julie E.; Nagilla, Rakesh; Nassau, Pamela M.; Ng, Sze-Ling; Ouellette, Michael T.; Pasikanti, Kishore K.; Potvain, Florent; Reilly, Michael A.; Rivera, Elizabeth J.; Sautet, Stephane; Schaeffer, Michelle C.; Sehon, Clark A.; Sun, Helen; Thorpe, James H.; Totoritis, Rachel D.; Ward, Paris; Wellaway, Natalie; Wisnoski, David D.; Woolven, James M.; Bertin, John; Marquis, Robert W.Journal of Medicinal Chemistry (2019), 62 (10), 5096-5110CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)RIP1 kinase regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including inflammatory and neurol. diseases. Currently, RIP1 kinase inhibitors have advanced into early clin. trials for evaluation in inflammatory diseases such as psoriasis, rheumatoid arthritis, and ulcerative colitis and neurol. diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. In this paper, we report on the design of potent and highly selective dihydropyrazole (DHP) RIP1 kinase inhibitors starting from a high-throughput screen and the lead-optimization of this series from a lead with minimal rat oral exposure to the identification of dihydropyrazole 77 with good pharmacokinetic profiles in multiple species. Addnl., we identified a potent murine RIP1 kinase inhibitor 76 as a valuable in vivo tool mol. suitable for evaluating the role of RIP1 kinase in chronic models of disease. DHP 76 showed efficacy in mouse models of both multiple sclerosis and human retinitis pigmentosa.
- 154Harris, P. A.; Marinis, J. M.; Lich, J. D.; Berger, S. B.; Chirala, A.; Cox, J. A.; Eidam, P. M.; Finger, J. N.; Gough, P. J.; Jeong, J. U.; Kang, J.; Kasparcova, V.; Leister, L. K.; Mahajan, M. K.; Miller, G.; Nagilla, R.; Ouellette, M. T.; Reilly, M. A.; Rendina, A. R.; Rivera, E. J.; Sun, H. H.; Thorpe, J. H.; Totoritis, R. D.; Wang, W.; Wu, D.; Zhang, D.; Bertin, J.; Marquis, R. W. Identification of a RIP1 kinase inhibitor clinical candidate (GSK3145095) for the treatment of pancreatic cancer. ACS Med. Chem. Lett. 2019, 10, 857– 862, DOI: 10.1021/acsmedchemlett.9b00108[ACS Full Text], [CAS], Google Scholar154https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXptFymu7g%253D&md5=3e4783b47ed7240e15ae537749f20f2fIdentification of a RIP1 Kinase Inhibitor Clinical Candidate (GSK3145095) for the Treatment of Pancreatic CancerHarris, Philip A.; Marinis, Jill M.; Lich, John D.; Berger, Scott B.; Chirala, Anirudh; Cox, Julie A.; Eidam, Patrick M.; Finger, Joshua N.; Gough, Peter J.; Jeong, Jae U.; Kang, James; Kasparcova, Viera; Leister, Lara K.; Mahajan, Mukesh K.; Miller, George; Nagilla, Rakesh; Ouellette, Michael T.; Reilly, Michael A.; Rendina, Alan R.; Rivera, Elizabeth J.; Sun, Helen H.; Thorpe, James H.; Totoritis, Rachel D.; Wang, Wei; Wu, Dongling; Zhang, Daohua; Bertin, John; Marquis, Robert W.ACS Medicinal Chemistry Letters (2019), 10 (6), 857-862CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)RIP1 regulates cell death and inflammation and is believed to play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases and cancer. While small-mol. inhibitors of RIP1 kinase have been advanced to the clinic for inflammatory diseases and CNS indications, RIP1 inhibitors for oncol. indications have yet to be described. Herein we report on the discovery and profile of GSK3145095 (compd. 6). Compd. 6 potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking RIP1 kinase-dependent cellular responses. Highlighting its potential as a novel cancer therapy, the inhibitor was also able to promote a tumor suppressive T cell phenotype in pancreatic adenocarcinoma organ cultures. Compd. 6 is currently in phase 1 clin. studies for pancreatic adenocarcinoma and other selected solid tumors.
- 155Mukherjee, T.; Hovingh, E. S.; Foerster, E. G.; Abdel-Nour, M.; Philpott, D. J.; Girardin, S. E. NOD1 and NOD2 in inflammation, immunity and disease. Arch. Biochem. Biophys. 2019, 670, 69– 81, DOI: 10.1016/j.abb.2018.12.022[Crossref], [PubMed], [CAS], Google Scholar155https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitFGlsL4%253D&md5=7ef01b0d9c2b3bd6b28e60508af3b9dcNOD1 and NOD2 in inflammation, immunity and diseaseMukherjee, Tapas; Hovingh, Elise Sofie; Foerster, Elisabeth G.; Abdel-Nour, Mena; Philpott, Dana J.; Girardin, Stephen E.Archives of Biochemistry and Biophysics (2019), 670 (), 69-81CODEN: ABBIA4; ISSN:0003-9861. (Elsevier B.V.)A review. NOD1 and NOD2 are related intracellular sensors of bacterial peptidoglycan and belong to the Nod-like receptor (NLR) family of innate immune proteins that play fundamental and pleiotropic roles in host defense against infection and in the control of inflammation. The importance of these proteins is also highlighted by the genetic assocn. between single nucleotide polymorphisms in NOD2 and susceptibility to Crohn's disease, an inflammatory bowel disease. At the cellular level, recent efforts have delineated the signaling pathways triggered following activation of NOD1 and NOD2, and the interplay with various cellular processes, such as autophagy. In vivo studies have revealed the importance of NOD-dependent host defense in models of infection, and a crucial area of investigation focuses on understanding the role of NOD1 and NOD2 at the intestinal mucosa, as this is of prime importance for understanding the etiol. of Crohn's disease.
- 156Caruso, R.; Warner, N.; Inohara, N.; Nunez, G. NOD1 and NOD2: signaling, host defense, and inflammatory disease. Immunity 2014, 41, 898– 908, DOI: 10.1016/j.immuni.2014.12.010[Crossref], [PubMed], [CAS], Google Scholar156https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXislyqsg%253D%253D&md5=da20e3b76c185e91da9168b011bc0b78NOD1 and NOD2: Signaling, Host Defense, and Inflammatory DiseaseCaruso, Roberta; Warner, Neil; Inohara, Naohiro; Nunez, GabrielImmunity (2014), 41 (6), 898-908CODEN: IUNIEH; ISSN:1074-7613. (Elsevier Inc.)A review. The nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2, the founding members of the intracellular NOD-like receptor family, sense conserved motifs in bacterial peptidoglycan and induce proinflammatory and antimicrobial responses. Here, we discuss recent developments about the mechanisms by which NOD1 and NOD2 are activated by bacterial ligands, the regulation of their signaling pathways, and their role in host defense and inflammatory disease. Several routes for the entry of peptidoglycan ligands to the host cytosol to trigger activation of NOD1 and NOD2 have been elucidated. Furthermore, genetic screens and biochem. analyses have revealed mechanisms that regulate NOD1 and NOD2 signaling. Finally, recent studies have suggested several mechanisms to account for the link between NOD2 variants and susceptibility to Crohn's disease. Further understanding of NOD1 and NOD2 should provide new insight into the pathogenesis of disease and the development of new strategies to treat inflammatory and infectious disorders.
- 157Tigno-Aranjuez, J. T.; Benderitter, P.; Rombouts, F.; Deroose, F.; Bai, X.; Mattioli, B.; Cominelli, F.; Pizarro, T. T.; Hoflack, J.; Abbott, D. W. In vivo inhibition of RIPK2 kinase alleviates inflammatory disease. J. Biol. Chem. 2014, 289, 29651– 29664, DOI: 10.1074/jbc.M114.591388[Crossref], [PubMed], [CAS], Google Scholar157https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVSmt77K&md5=db1b6a092a8f61888702db41576892a9In Vivo Inhibition of RIPK2 Kinase Alleviates Inflammatory DiseaseTigno-Aranjuez, Justine T.; Benderitter, Pascal; Rombouts, Frederik; Deroose, Frederik; Bai, XiaoDong; Mattioli, Benedetta; Cominelli, Fabio; Pizarro, Theresa T.; Hoflack, Jan; Abbott, Derek W.Journal of Biological Chemistry (2014), 289 (43), 29651-29664CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)The RIPK2 kinase transduces signaling downstream of the intracellular peptidoglycan sensors NOD1 and NOD2 to promote a productive inflammatory response. However, excessive NOD2 signaling has been assocd. with numerous diseases, including inflammatory bowel disease (IBD), sarcoidosis and inflammatory arthritis, making pharmacol. inhibition of RIPK2 an appealing strategy. In this work, the authors report the generation, identification, and evaluation of novel RIPK2 specific inhibitors. These compds. potently inhibit the RIPK2 tyrosine kinase activity in in vitro biochem. assays and cellular assays, as well as effectively reduce RIPK2-mediated effects in an in vivo peritonitis model. In conjunction with the development of these inhibitors, the authors have also defined a panel of genes whose expression is regulated by RIPK2 kinase activity. Such RIPK2 activation markers may serve as a useful tool for predicting settings likely to benefit from RIPK2 inhibition. Using these markers and the FDA-approved RIPK2 inhibitor Gefitinib, the authors show that pharmacol. RIPK2 inhibition drastically improves disease in a spontaneous model of Crohn Disease-like ileitis. Furthermore, using novel RIPK2-specific inhibitors, the authors show that cellular recruitment is inhibited in an in vivo peritonitis model. Altogether, the data presented in this work provides a strong rationale for further development and optimization of RIPK2-targeted pharmaceuticals and diagnostics.
- 158Haile, P. A.; Votta, B. J.; Marquis, R. W.; Bury, M. J.; Mehlmann, J. F.; Singhaus, R., Jr.; Charnley, A. K.; Lakdawala, A. S.; Convery, M. A.; Lipshutz, D. B.; Desai, B. M.; Swift, B.; Capriotti, C. A.; Berger, S. B.; Mahajan, M. K.; Reilly, M. A.; Rivera, E. J.; Sun, H. H.; Nagilla, R.; Beal, A. M.; Finger, J. N.; Cook, M. N.; King, B. W.; Ouellette, M. T.; Totoritis, R. D.; Pierdomenico, M.; Negroni, A.; Stronati, L.; Cucchiara, S.; Ziolkowski, B.; Vossenkamper, A.; MacDonald, T. T.; Gough, P. J.; Bertin, J.; Casillas, L. N. The identification and pharmacological characterization of 6-(tert-butylsulfonyl)-N-(5-fluoro-1h-indazol-3-yl)quinolin-4-amine (GSK583), a highly potent and selective inhibitor of RIP2 kinase. J. Med. Chem. 2016, 59, 4867– 4880, DOI: 10.1021/acs.jmedchem.6b00211[ACS Full Text], [CAS], Google Scholar158https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xms1GqsLs%253D&md5=74a178c9f055232de8a729bd254fce3eThe Identification and Pharmacological Characterization of 6-(tert-Butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine (GSK583), a Highly Potent and Selective Inhibitor of RIP2 KinaseHaile, Pamela A.; Votta, Bartholomew J.; Marquis, Robert W.; Bury, Michael J.; Mehlmann, John F.; Singhaus, Robert; Charnley, Adam K.; Lakdawala, Ami S.; Convery, Maire A.; Lipshutz, David B.; Desai, Biva M.; Swift, Barbara; Capriotti, Carol A.; Berger, Scott B.; Majahan, Mukesh K.; Reilly, Michael A.; Rivera, Elizabeth J.; Sun, Helen H.; Nagilla, Rakesh; Beal, Allison M.; Finger, Joshua N.; Cook, Michael N.; King, Bryan W.; Ouellette, Michael T.; Totoritis, Rachel D.; Pierdomenico, Maria; Negroni, Anna; Stronati, Laura; Cucchiara, Salvatore; Ziolkowski, Bartlomiej; Vossenkamper, Anna; MacDonald, Thomas T.; Gough, Peter J.; Bertin, John; Casillas, Linda N.Journal of Medicinal Chemistry (2016), 59 (10), 4867-4880CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)RIP2 kinase is a central component of the innate immune system and enables downstream signaling following activation of the pattern recognition receptors NOD1 and NOD2, leading to the prodn. of inflammatory cytokines. Recently, several inhibitors of RIP2 kinase have been disclosed that have contributed to the fundamental understanding of the role of RIP2 in this pathway. However, because they lack either broad kinase selectivity or strong affinity for RIP2, these tools have only limited utility to assess the role of RIP2 in complex environments. We present, herein, the discovery and pharmacol. characterization of GSK583 (I), a next-generation RIP2 inhibitor possessing exquisite selectivity and potency. Having demonstrated the pharmacol. precision of this tool compd., we report its use in elucidating the role of RIP2 kinase in a variety of in vitro, in vivo, and ex vivo expts., further clarifying our understanding of the role of RIP2 in NOD1 and NOD2 mediated disease pathogenesis.
- 159Haile, P. A.; Casillas, L. N.; Bury, M. J.; Mehlmann, J. F.; Singhaus, R., Jr.; Charnley, A. K.; Hughes, T. V.; DeMartino, M. P.; Wang, G. Z.; Romano, J. J.; Dong, X.; Plotnikov, N. V.; Lakdawala, A. S.; Convery, M. A.; Votta, B. J.; Lipshutz, D. B.; Desai, B. M.; Swift, B.; Capriotti, C. A.; Berger, S. B.; Mahajan, M. K.; Reilly, M. A.; Rivera, E. J.; Sun, H. H.; Nagilla, R.; LePage, C.; Ouellette, M. T.; Totoritis, R. D.; Donovan, B. T.; Brown, B. S.; Chaudhary, K. W.; Gough, P. J.; Bertin, J.; Marquis, R. W. Identification of quinoline-based RIP2 kinase inhibitors with an improved therapeutic index to the herg ion channel. ACS Med. Chem. Lett. 2018, 9, 1039– 1044, DOI: 10.1021/acsmedchemlett.8b00344[ACS Full Text], [CAS], Google Scholar159https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslyjsrnJ&md5=64f2cfeb587cf336339fe800ce5cb96bIdentification of Quinoline-Based RIP2 Kinase Inhibitors with an Improved Therapeutic Index to the hERG Ion ChannelHaile, Pamela A.; Casillas, Linda N.; Bury, Michael J.; Mehlmann, John F.; Singhaus, Robert; Charnley, Adam K.; Hughes, Terry V.; DeMartino, Michael P.; Wang, Gren Z.; Romano, Joseph J.; Dong, Xiaoyang; Plotnikov, Nikolay V.; Lakdawala, Ami S.; Convery, Maire A.; Votta, Bartholomew J.; Lipshutz, David B.; Desai, Biva M.; Swift, Barbara; Capriotti, Carol A.; Berger, Scott B.; Mahajan, Mukesh K.; Reilly, Michael A.; Rivera, Elizabeth J.; Sun, Helen H.; Nagilla, Rakesh; LePage, Carol; Ouellette, Michael T.; Totoritis, Rachel D.; Donovan, Brian T.; Brown, Barry S.; Chaudhary, Khuram W.; Gough, Peter J.; Bertin, John; Marquis, Robert W.ACS Medicinal Chemistry Letters (2018), 9 (10), 1039-1044CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)RIP2 kinase was recently identified as a therapeutic target for a variety of autoimmune diseases. We have reported previously a selective 4-aminoquinoline-based RIP2 inhibitor GSK583 and demonstrated its effectiveness in blocking downstream NOD2 signaling in cellular models, rodent in vivo models, and human ex vivo disease models. While this tool compd. was valuable in validating the biol. pathway, it suffered from activity at the hERG ion channel and a poor PK/PD profile thereby limiting progression of this analog. Herein, we detail our efforts to improve both this off-target liability as well as the PK/PD profile of this series of inhibitors through modulation of lipophilicity and strengthening hinge binding ability. These efforts have led to inhibitor I, which possesses high binding affinity for the ATP pocket of RIP2 (IC50 = 1 nM) and inhibition of downstream cytokine prodn. in human whole blood (IC50 = 10 nM) with reduced hERG activity (14 μM).
- 160Haile, P. A.; Casillas, L. N.; Votta, B. J.; Wang, G. Z.; Charnley, A. K.; Dong, X.; Bury, M. J.; Romano, J. J.; Mehlmann, J. F.; King, B. W.; Erhard, K. F.; Hanning, C. R.; Lipshutz, D. B.; Desai, B. M.; Capriotti, C. A.; Schaeffer, M. C.; Berger, S. B.; Mahajan, M. K.; Reilly, M. A.; Nagilla, R.; Rivera, E. J.; Sun, H. H.; Kenna, J. K.; Beal, A. M.; Ouellette, M. T.; Kelly, M.; Stemp, G.; Convery, M. A.; Vossenkamper, A.; MacDonald, T. T.; Gough, P. J.; Bertin, J.; Marquis, R. W. Discovery of a first-in-class Receptor interacting protein 2 (RIP2) kinase specific clinical candidate, 2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl dihydrogen phosphate, for the treatment of inflammatory diseases. J. Med. Chem. 2019, 62, 6482– 6494, DOI: 10.1021/acs.jmedchem.9b00575[ACS Full Text], [CAS], Google Scholar160https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtlams77M&md5=c25c648d6ff1d2f1c149e4c37c712026Discovery of a First-in-Class Receptor Interacting Protein 2 (RIP2) Kinase Specific Clinical Candidate, 2-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl Dihydrogen Phosphate, for the Treatment of Inflammatory DiseasesHaile, Pamela A.; Casillas, Linda N.; Votta, Bartholomew J.; Wang, Gren Z.; Charnley, Adam K.; Dong, Xiaoyang; Bury, Michael J.; Romano, Joseph J.; Mehlmann, John F.; King, Bryan W.; Erhard, Karl F.; Hanning, Charles R.; Lipshutz, David B.; Desai, Biva M.; Capriotti, Carol A.; Schaeffer, Michelle C.; Berger, Scott B.; Mahajan, Mukesh K.; Reilly, Michael A.; Nagilla, Rakesh; Rivera, Elizabeth J.; Sun, Helen H.; Kenna, John K.; Beal, Allison M.; Ouellette, Michael T.; Kelly, Mike; Stemp, Gillian; Convery, Maire A.; Vossenkamper, Anna; MacDonald, Thomas T.; Gough, Peter J.; Bertin, John; Marquis, Robert W.Journal of Medicinal Chemistry (2019), 62 (14), 6482-6494CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)RIP2 kinase has been identified as a key signal transduction partner in the NOD2 pathway contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-mol. inhibitors of RIP2 kinase or its signaling partners on the NOD2 pathway that are suitable for advancement into the clinic have yet to be described. Herein, we report our discovery and profile of the prodrug clin. compd., inhibitor 3, currently in phase 1 clin. studies. Compd. 3 potently binds to RIP2 kinase with good kinase specificity and has excellent activity in blocking many proinflammatory cytokine responses in vivo and in human IBD explant samples. The highly favorable physicochem. and ADMET properties of 3 combined with high potency led to a predicted low oral dose in humans.
- 161Haffner, C. D.; Charnley, A. K.; Aquino, C. J.; Casillas, L.; Convery, M. A.; Cox, J. A.; Elban, M. A.; Goodwin, N. C.; Gough, P. J.; Haile, P. A.; Hughes, T. V.; Knapp-Reed, B.; Kreatsoulas, C.; Lakdawala, A. S.; Li, H.; Lian, Y.; Lipshutz, D.; Mehlmann, J. F.; Ouellette, M.; Romano, J.; Shewchuk, L.; Shu, A.; Votta, B. J.; Zhou, H.; Bertin, J.; Marquis, R. W. Discovery of pyrazolocarboxamides as potent and selective Receptor interacting protein 2 (RIP2) kinase inhibitors. ACS Med. Chem. Lett. 2019, 10, 1518– 1523, DOI: 10.1021/acsmedchemlett.9b00141[ACS Full Text], [CAS], Google Scholar161https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFChs77P&md5=8e77a9908acc704196eee7d336f67c62Discovery of Pyrazolocarboxamides as Potent and Selective Receptor Interacting Protein 2 (RIP2) Kinase InhibitorsHaffner, Curt D.; Charnley, Adam K.; Aquino, Christopher J.; Casillas, Linda; Convery, Maire A.; Cox, Julie A.; Elban, Mark A.; Goodwin, Nicole C.; Gough, Peter J.; Haile, Pamela A.; Hughes, Terry V.; Knapp-Reed, Beth; Kreatsoulas, Constantine; Lakdawala, Ami S.; Li, Huijie; Lian, Yiqian; Lipshutz, David; Mehlmann, John F.; Ouellette, Michael; Romano, Joseph; Shewchuk, Lisa; Shu, Arthur; Votta, Bartholomew J.; Zhou, Huiqiang; Bertin, John; Marquis, Robert W.ACS Medicinal Chemistry Letters (2019), 10 (11), 1518-1523CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Herein we report the discovery of pyrazolocarboxamides as novel, potent, and kinase selective inhibitors of receptor interacting protein 2 kinase (RIP2). Fragment based screening and design principles led to the identification of the inhibitor series, and X-ray crystallog. was used to inform key structural changes. Through key substitutions about the N1 and C5 N positions on the pyrazole ring significant kinase selectivity and potency were achieved. Bridged bicyclic pyrazolocarboxamide 11 represents a selective and potent inhibitor of RIP2 and will allow for a more detailed investigation of RIP2 inhibition as a therapeutic target for autoinflammatory disorders.
- 162He, X.; Da Ros, S.; Nelson, J.; Zhu, X.; Jiang, T.; Okram, B.; Jiang, S.; Michellys, P. Y.; Iskandar, M.; Espinola, S.; Jia, Y.; Bursulaya, B.; Kreusch, A.; Gao, M. Y.; Spraggon, G.; Baaten, J.; Clemmer, L.; Meeusen, S.; Huang, D.; Hill, R.; Nguyen-Tran, V.; Fathman, J.; Liu, B.; Tuntland, T.; Gordon, P.; Hollenbeck, T.; Ng, K.; Shi, J.; Bordone, L.; Liu, H. Identification of potent and selective RIPK2 inhibitors for the treatment of inflammatory diseases. ACS Med. Chem. Lett. 2017, 8, 1048– 1053, DOI: 10.1021/acsmedchemlett.7b00258[ACS Full Text], [CAS], Google Scholar162https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFOjtLjJ&md5=87e32df13c63a9cd16b20652ae96b36aIdentification of Potent and Selective RIPK2 Inhibitors for the Treatment of Inflammatory DiseasesHe, Xiaohui; Da Ros, Sara; Nelson, John; Zhu, Xuefeng; Jiang, Tao; Okram, Barun; Jiang, Songchun; Michellys, Pierre-Yves; Iskandar, Maya; Espinola, Sheryll; Jia, Yong; Bursulaya, Badry; Kreusch, Andreas; Gao, Mu-Yun; Spraggon, Glen; Baaten, Janine; Clemmer, Leah; Meeusen, Shelly; Huang, David; Hill, Robert; Nguyen-Tran, Van; Fathman, John; Liu, Bo; Tuntland, Tove; Gordon, Perry; Hollenbeck, Thomas; Ng, Kenneth; Shi, Jian; Bordone, Laura; Liu, HongACS Medicinal Chemistry Letters (2017), 8 (10), 1048-1053CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)NOD2 (nucleotide-binding oligomerization domain-contg. protein 2) is an internal pattern recognition receptor that recognizes bacterial peptidoglycan and stimulates host immune responses. Dysfunction of NOD2 pathway has been assocd. with a no. of autoinflammatory disorders. To date, direct inhibitors of NOD2 have not been described due to tech. challenges of targeting the oligomeric protein complex. Receptor interacting protein kinase 2 (RIPK2) is an intracellular serine/threonine/tyrosine kinase, a key signaling partner, and an obligate kinase for NOD2. As such, RIPK2 represents an attractive target to probe the pathol. roles of NOD2 pathway. To search for selective RIPK2 inhibitors, the authors employed virtual library screening (VLS) and structure based design that eventually led to a potent and selective RIPK2 inhibitor 8 (4-(7-ethoxy-6-(isopropylsulfonyl)imidazo[1,2-a]pyridin-3-yl)-6-fluoropyridin-2-amine) with excellent oral bioavailability, which was used to evaluate the effects of inhibition of RIPK2 in various in vitro assays and ex vivo and in vivo pharmacodynamic models.
- 163Suzuki, N.; Suzuki, S.; Duncan, G. S.; Millar, D. G.; Wada, T.; Mirtsos, C.; Takada, H.; Wakeham, A.; Itie, A.; Li, S.; Penninger, J. M.; Wesche, H.; Ohashi, P. S.; Mak, T. W.; Yeh, W. C. Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Nature 2002, 416, 750– 756, DOI: 10.1038/nature736[Crossref], [PubMed], [CAS], Google Scholar163https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XjtVKksb4%253D&md5=3cab6526ac8aa58532f50c5bfb364e5cSevere impairment of interleukin-1 and Toll-like receptor signaling in mice lacking IRAK-4Suzuki, N.; Suzuki, S.; Duncan, G. S.; Millar, D. G.; Wada, T.; Mirtsos, C.; Takada, H.; Wakeham, A.; Itie, A.; Li, S.; Penninger, J. M.; Wesche, H.; Ohashi, P. S.; Mak, T. W.; Yeh, W. C.Nature (London, United Kingdom) (2002), 416 (6882), 750-756CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Toll-like receptors (TLRs), which recognize pathogen-assocd. mol. patterns, and members of the pro-inflammatory interleukin-1 receptor (IL-1R) family, share homologies in their cytoplasmic domains called Toll/IL-1R/plant R gene homol. (TIR) domains. Intracellular signaling mechanisms mediated by TLRs are similar, with MyD88 and TRAF6 having crit. roles. Signal transduction between MyD88 and TRAF6 is known to involve the serine-threonine kinase IL-1 receptor-assocd. kinase 1 (IRAK-1) and two homologous proteins, IRAK-2 and IRAK-M. However, the physiol. functions of the IRAK mols. remain unclear, and gene-targeting studies have shown that IRAK-1 is only partially required for IL-1R and TLR signaling. Here we show by gene-targeting that IRAK-4, an IRAK mol. closely related to the Drosophila Pelle protein, is indispensable for the responses of animals and cultured cells to IL-1 and ligands that stimulate various TLRs. IRAK-4-deficient animals are completely resistant to a LD of lipopolysaccharide (LPS). In addn., animals lacking IRAK-4 are severely impaired in their responses to viral and bacterial challenges. Our results indicate that IRAK-4 has an essential role in innate immunity.
- 164Ku, C. L.; von Bernuth, H.; Picard, C.; Zhang, S. Y.; Chang, H. H.; Yang, K.; Chrabieh, M.; Issekutz, A. C.; Cunningham, C. K.; Gallin, J.; Holland, S. M.; Roifman, C.; Ehl, S.; Smart, J.; Tang, M.; Barrat, F. J.; Levy, O.; McDonald, D.; Day-Good, N. K.; Miller, R.; Takada, H.; Hara, T.; Al-Hajjar, S.; Al-Ghonaium, A.; Speert, D.; Sanlaville, D.; Li, X.; Geissmann, F.; Vivier, E.; Marodi, L.; Garty, B. Z.; Chapel, H.; Rodriguez-Gallego, C.; Bossuyt, X.; Abel, L.; Puel, A.; Casanova, J. L. Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity. J. Exp. Med. 2007, 204, 2407– 2422, DOI: 10.1084/jem.20070628[Crossref], [PubMed], [CAS], Google Scholar164https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFCntrbP&md5=995f31b8684f666d83b752908323ce1eSelective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunityKu, Cheng-Lung; von Bernuth, Horst; Picard, Capucine; Zhang, Shen-Ying; Chang, Huey-Hsuan; Yang, Kun; Chrabieh, Maya; Issekutz, Andrew C.; Cunningham, Coleen K.; Gallin, John; Holland, Steven M.; Roifman, Chaim; Ehl, Stephan; Smart, Joanne; Tang, Mimi; Barrat, Franck J.; Levy, Ofer; McDonald, Douglas; Day-Good, Noorbibi K.; Miller, Richard; Takada, Hidetoshi; Hara, Toshiro; Al-Hajjar, Sami; Al-Ghonaium, Abdulaziz; Speert, David; Sanlaville, Damien; Li, Xiaoxia; Geissmann, Frederic; Vivier, Eric; Marodi, Laszlo; Garty, Ben-Zion; Chapel, Helen; Rodriguez-Gallego, Carlos; Bossuyt, Xavier; Abel, Laurent; Puel, Anne; Casanova, Jean-LaurentJournal of Experimental Medicine (2007), 204 (10), 2407-2422CODEN: JEMEAV; ISSN:0022-1007. (Rockefeller University Press)Human interleukin (IL) 1 receptor-assocd. kinase 4 (IRAK-4) deficiency is a recently discovered primary immunono-deficiency that impairs Toll/IL-1R immunity, except for the Toll-like receptor (TLR) 3- an TLR4-interferon (IRN)-α/β pathways. The clin. and immunol. phenotype remains largely unknown. We diagnose up to 28 patients with IRAK-4 deficiency, tested blood TLR responses for individual leukocyte subsets, and TLR responses for multiple cytokines. The patients' peripheral blood mononuclear cells (PBMCs) did not induce the 11 non-IFN cytokines tested upon activation with TLR agonists other than the nonspecific TLR3 agonist poly(I:C). The patients' individual cell subsets from both myeloid (granulocytes, monocytes, monocyte-derived dendritic cells [MDDCs], myeloid DCs [MDCs], and plasmacytoid DCs) and lymphoid (B, T, and NK cells) lineages did not respond to the TLR agonists that stimulated control cells, with the exception of residual responses to poly(I:C) and lipopolysaccharide in MDCs and MDDCs. Most patients (22 out of 28; 79%) suffered from invasive pneumococcal disease, which was often recurrent (13 out of 22; 59%). Other infections were rare, with the exception of severe staphylococcal disease (9 out of 28; 32%). Almost half of the patients died (12 out of 28; 43%). No death and no invasive infection occurred in patients older than 8 and 14 yr. resp. The IRAK-4-dependent TLRs and IL-1Rs are therefore vital for childhood immunity to pyogenic bacteria, particularly Streptococcus pneumoniae. Conversely, IRAK-4-dependent human TLRs appear to play a redundant role in protective immunity to most infections, at most limited to childhood immunity to some pyogenic bacteria.
- 165Chaudhary, D.; Robinson, S.; Romero, D. L. Recent advances in the discovery of small molecule inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4) as a therapeutic target for inflammation and oncology disorders. J. Med. Chem. 2015, 58, 96– 110, DOI: 10.1021/jm5016044[ACS Full Text], [CAS], Google Scholar165https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVCjsLzL&md5=795797f7f3f07597ecd0b5899498804bRecent Advances in the Discovery of Small Molecule Inhibitors of Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) as a Therapeutic Target for Inflammation and Oncology DisordersChaudhary, Divya; Robinson, Shaughnessy; Romero, Donna L.Journal of Medicinal Chemistry (2015), 58 (1), 96-110CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. IRAK4, a serine/threonine kinase, plays a key role in both inflammation and oncol. diseases. Herein, we summarize the compelling biol. surrounding the IRAK4 signaling node in disease, review key structural features of IRAK4 including selectivity challenges, and describe efforts to discover clin. viable IRAK4 inhibitors. Finally, a view of knowledge gained and remaining challenges is provided.
- 166Dudhgaonkar, S.; Ranade, S.; Nagar, J.; Subramani, S.; Prasad, D. S.; Karunanithi, P.; Srivastava, R.; Venkatesh, K.; Selvam, S.; Krishnamurthy, P.; Mariappan, T. T.; Saxena, A.; Fan, L.; Stetsko, D. K.; Holloway, D. A.; Li, X.; Zhu, J.; Yang, W. P.; Ruepp, S.; Nair, S.; Santella, J.; Duncia, J.; Hynes, J.; McIntyre, K. W.; Carman, J. A. Selective IRAK4 inhibition attenuates disease in murine lupus models and demonstrates steroid sparing activity. J. Immunol. 2017, 198, 1308– 1319, DOI: 10.4049/jimmunol.1600583[Crossref], [PubMed], [CAS], Google Scholar166https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtlaitb8%253D&md5=340ba834510cd04eb0e984e212731e17Selective IRAK4 Inhibition Attenuates Disease in Murine Lupus Models and Demonstrates Steroid Sparing ActivityDudhgaonkar, Shailesh; Ranade, Sourabh; Nagar, Jignesh; Subramani, Siva; Prasad, Durga Shiv; Karunanithi, Preethi; Srivastava, Ratika; Venkatesh, Kamala; Selvam, Sabariya; Krishnamurthy, Prasad; Mariappan, T. Thanga; Saxena, Ajay; Fan, Li; Stetsko, Dawn K.; Holloway, Deborah A.; Li, Xin; Zhu, Jun; Yang, Wen-Pin; Ruepp, Stefan; Nair, Satheesh; Santella, Joseph; Duncia, John; Hynes, John; McIntyre, Kim W.; Carman, Julie A.Journal of Immunology (2017), 198 (3), 1308-1319CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)The serine/threonine kinase IL-1R-assocd. kinase (IRAK)4 is a crit. regulator of innate immunity. We have identified BMS-986126, a potent, highly selective inhibitor of IRAK4 kinase activity that demonstrates equipotent activity against multiple MyD88-dependent responses both in vitro and in vivo. BMS-986126 failed to inhibit assays downstream of MyD88-independent receptors, including the TNF receptor and TLR3. Very little activity was seen downstream of TLR4, which can also activate an MyD88-independent pathway. In mice, the compd. inhibited cytokine prodn. induced by injection of several different TLR agonists, including those for TLR2, TLR7, and TLR9. The compd. also significantly suppressed skin inflammation induced by topical administration of the TLR7 agonist imiquimod. BMS-986126 demonstrated robust activity in the MRL/lpr and NZB/NZW models of lupus, inhibiting multiple pathogenic responses. In the MRL/lpr model, robust activity was obsd. with the combination of suboptimal doses of BMS-986126 and prednisolone, suggesting the potential for steroid sparing activity. BMS-986126 also demonstrated synergy with prednisolone in assays of TLR7- and TLR9-induced IFN target gene expression using human PBMCs. Lastly, BMS-986126 inhibited TLR7- and TLR9-dependent responses using cells derived from lupus patients, suggesting that inhibition of IRAK4 has the potential for therapeutic benefit in treating lupus.
- 167Lee, K. L.; Ambler, C. M.; Anderson, D. R.; Boscoe, B. P.; Bree, A. G.; Brodfuehrer, J. I.; Chang, J. S.; Choi, C.; Chung, S.; Curran, K. J.; Day, J. E.; Dehnhardt, C. M.; Dower, K.; Drozda, S. E.; Frisbie, R. K.; Gavrin, L. K.; Goldberg, J. A.; Han, S.; Hegen, M.; Hepworth, D.; Hope, H. R.; Kamtekar, S.; Kilty, I. C.; Lee, A.; Lin, L. L.; Lovering, F. E.; Lowe, M. D.; Mathias, J. P.; Morgan, H. M.; Murphy, E. A.; Papaioannou, N.; Patny, A.; Pierce, B. S.; Rao, V. R.; Saiah, E.; Samardjiev, I. J.; Samas, B. M.; Shen, M. W. H.; Shin, J. H.; Soutter, H. H.; Strohbach, J. W.; Symanowicz, P. T.; Thomason, J. R.; Trzupek, J. D.; Vargas, R.; Vincent, F.; Yan, J.; Zapf, C. W.; Wright, S. W. Discovery of clinical candidate 1-{[(2s,3s,4s)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a potent, selective inhibitor of interleukin-1 receptor associated kinase 4 (IRAK4), by fragment-based drug design. J. Med. Chem. 2017, 60, 5521– 5542, DOI: 10.1021/acs.jmedchem.7b00231[ACS Full Text], [CAS], Google Scholar167https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnslGqu7c%253D&md5=9771ad2d33089f6ef3dba3556536ff1aDiscovery of Clinical Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug DesignLee, Katherine L.; Ambler, Catherine M.; Anderson, David R.; Boscoe, Brian P.; Bree, Andrea G.; Brodfuehrer, Joanne I.; Chang, Jeanne S.; Choi, Chulho; Chung, Seungwon; Curran, Kevin J.; Day, Jacqueline E.; Dehnhardt, Christoph M.; Dower, Ken; Drozda, Susan E.; Frisbie, Richard K.; Gavrin, Lori K.; Goldberg, Joel A.; Han, Seungil; Hegen, Martin; Hepworth, David; Hope, Heidi R.; Kamtekar, Satwik; Kilty, Iain C.; Lee, Arthur; Lin, Lih-Ling; Lovering, Frank E.; Lowe, Michael D.; Mathias, John P.; Morgan, Heidi M.; Murphy, Elizabeth A.; Papaioannou, Nikolaos; Patny, Akshay; Pierce, Betsy S.; Rao, Vikram R.; Saiah, Eddine; Samardjiev, Ivan J.; Samas, Brian M.; Shen, Marina W. H.; Shin, Julia H.; Soutter, Holly H.; Strohbach, Joseph W.; Symanowicz, Peter T.; Thomason, Jennifer R.; Trzupek, John D.; Vargas, Richard; Vincent, Fabien; Yan, Jiangli; Zapf, Christoph W.; Wright, Stephen W.Journal of Medicinal Chemistry (2017), 60 (13), 5521-5542CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topol. in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chem. effort featured the judicious placement of lipophilicity, informed by cocrystal structures with IRAK4 and optimization of ADME properties to deliver clin. candidate I. This compd. benefitted from a 5-unit increase in lipophilic efficiency from the fragment hit, excellent kinase selectivity, and pharmacokinetic properties suitable for oral administration.
- 168Kelly, P. N.; Romero, D. L.; Yang, Y.; Shaffer, A. L., 3rd; Chaudhary, D.; Robinson, S.; Miao, W.; Rui, L.; Westlin, W. F.; Kapeller, R.; Staudt, L. M. Selective interleukin-1 receptor-associated kinase 4 inhibitors for the treatment of autoimmune disorders and lymphoid malignancy. J. Exp. Med. 2015, 212, 2189– 2201, DOI: 10.1084/jem.20151074[Crossref], [PubMed], [CAS], Google Scholar168https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XjtlSgu7s%253D&md5=cf477aff5f649644017cbe5330995a70Selective interleukin-1 receptor-associated kinase 4 inhibitors for the treatment of autoimmune disorders and lymphoid malignancyKelly, Priscilla N.; Romero, Donna L.; Yang, Yibin; Shaffer, Arthur L., III; Chaudhary, Divya; Robinson, Shaughnessy; Miao, Wenyan; Rui, Lixin; Westlin, William F.; Kapeller, Rosana; Staudt, Louis M.Journal of Experimental Medicine (2015), 212 (13), 2189-2201CODEN: JEMEAV; ISSN:1540-9538. (Rockefeller University Press)Pathol. activation of the Toll-like receptor signaling adaptor protein MYD88 underlies many autoimmune and inflammatory disease states. In the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLB CL), the oncogenic MYD88 L265P mutation occurs in 29% of cases, making it the most prevalent activating mutation in this malignancy. IRAK4 kinase accounts for almost all of the biol. functions of MYD88, highlighting IRAK4 as a therapeutic target for diseases driven by aberrant MYD88 signaling. Using innovative structure-based drug design methodologies, we report the development of highly selective and bioavailable small mol. IRAK4 inhibitors, ND-2158 and ND-2110. These small mols. suppressed LPS-induced TNF prodn., alleviated collagen-induced arthritis, and blocked gout formation in mouse models. IRAK4 inhibition promoted killing of ABC DLB CL lines harboring MYD88 L265P, by down-modulating survival signals, including NF-κB and autocrine IL-6/IL-10 engagement of the JAK-STAT3 pathway. In ABC DLB CL xenograft models, IRAK4 inhibition suppressed tumor growth as a single agent, and in combination with the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib or the Bcl-2 inhibitor ABT-199. Our findings support pharmacol. inhibition of IRAK4 as a therapeutic strategy in autoimmune disorders, in a genetically defined population of ABC DLB CL, and possibly other malignancies dependent on aberrant MYD88 signaling.
- 169Scott, J. S.; Degorce, S. L.; Anjum, R.; Culshaw, J.; Davies, R. D. M.; Davies, N. L.; Dillman, K. S.; Dowling, J. E.; Drew, L.; Ferguson, A. D.; Groombridge, S. D.; Halsall, C. T.; Hudson, J. A.; Lamont, S.; Lindsay, N. A.; Marden, S. K.; Mayo, M. F.; Pease, J. E.; Perkins, D. R.; Pink, J. H.; Robb, G. R.; Rosen, A.; Shen, M.; McWhirter, C.; Wu, D. Discovery and optimization of pyrrolopyrimidine inhibitors of interleukin-1 receptor associated kinase 4 (IRAK4) for the treatment of mutant MyD88(L265P) diffuse large B-cell lymphoma. J. Med. Chem. 2017, 60, 10071– 10091, DOI: 10.1021/acs.jmedchem.7b01290[ACS Full Text], [CAS], Google Scholar169https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVOitrjO&md5=9760f425ec33b238a43e1de0ec6d24f1Discovery and Optimization of Pyrrolopyrimidine Inhibitors of Interleukin-1 Receptor Associated Kinase 4 (IRAK4) for the Treatment of Mutant MYD88L265P Diffuse Large B-Cell LymphomaScott, James S.; Degorce, Sebastien L.; Anjum, Rana; Culshaw, Janet; Davies, Robert D. M.; Davies, Nichola L.; Dillman, Keith S.; Dowling, James E.; Drew, Lisa; Ferguson, Andrew D.; Groombridge, Sam D.; Halsall, Christopher T.; Hudson, Julian A.; Lamont, Scott; Lindsay, Nicola A.; Marden, Stacey K.; Mayo, Michele F.; Pease, J. Elizabeth; Perkins, David R.; Pink, Jennifer H.; Robb, Graeme R.; Rosen, Alan; Shen, Minhui; McWhirter, Claire; Wu, DedongJournal of Medicinal Chemistry (2017), 60 (24), 10071-10091CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Herein we report the optimization of a series of pyrrolopyrimidine inhibitors of interleukin-1 receptor assocd. kinase 4 (IRAK4) using x-ray crystal structures and structure based design to identify and optimize our scaffold. Compd. 28 demonstrated a favorable physicochem. and kinase selectivity profile and was identified as a promising in vivo tool with which to explore the role of IRAK4 inhibition in the treatment of mutant MYD88L265P diffuse large B-cell lymphoma (DLBCL). Compd. 28 was shown to be capable of demonstrating inhibition of NF-κB activation and growth of the ABC subtype of DLBCL cell lines in vitro at high concns. but showed greater effects in combination with a BTK inhibitor at lower concns. In vivo, the combination of compd. 28 and ibrutinib led to tumor regression in an ABC-DLBCL mouse model.
- 170Degorce, S. L.; Anjum, R.; Bloecher, A.; Carbajo, R. J.; Dillman, K. S.; Drew, L.; Halsall, C. T.; Lenz, E. M.; Lindsay, N. A.; Mayo, M. F.; Pink, J. H.; Robb, G. R.; Rosen, A.; Scott, J. S.; Xue, Y. Discovery of a series of 5-azaquinazolines as orally efficacious IRAK4 inhibitors targeting MyD88L265P mutant diffuse large B cell lymphoma. J. Med. Chem. 2019, 62, 9918– 9930, DOI: 10.1021/acs.jmedchem.9b01346[ACS Full Text], [CAS], Google Scholar170https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFyitLzE&md5=5029cfe2e62ca9bc3e7e9a0b02ab8cc0Discovery of a Series of 5-Azaquinazolines as Orally Efficacious IRAK4 Inhibitors Targeting MyD88L265P Mutant Diffuse Large B Cell LymphomaDegorce, Sebastien L.; Anjum, Rana; Bloecher, Andrew; Carbajo, Rodrigo J.; Dillman, Keith S.; Drew, Lisa; Halsall, Christopher T.; Lenz, Eva M.; Lindsay, Nicola A.; Mayo, Michele F.; Pink, Jennifer H.; Robb, Graeme R.; Rosen, Alan; Scott, James S.; Xue, YafengJournal of Medicinal Chemistry (2019), 62 (21), 9918-9930CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)In this article, the authors report the discovery of a series of 5-azaquinazolines as selective IRAK4 inhibitors. From modestly potent quinazoline 4, the authors introduced a 5-aza substitution to mask the 4-NH hydrogen bond donor (HBD). This allowed us to substitute the core with a 2-aminopyrazole, which showed large gains in cellular potency despite the addnl. formal HBD. Further optimization led to 6-cyanomethyl-5-azaquinazoline 13, a selective IRAK4 inhibitor which proved efficacious in combination with ibrutinib, while showing very little activity as a single agent up to 100 mg/kg. This contrasted to previously reported IRAK4 inhibitors that exhibited efficacy in the same model as single agents, and was attributed to the enhanced specificity of 13 towards IRAK4.
- 171Nair, S.; Kumar, S. R.; Paidi, V. R.; Sistla, R.; Kantheti, D.; Polimera, S. R.; Thangavel, S.; Mukherjee, A. J.; Das, M.; Bhide, R. S.; Pitts, W. J.; Murugesan, N.; Dudhgoankar, S.; Nagar, J.; Subramani, S.; Mazumder, D.; Carman, J. A.; Holloway, D. A.; Li, X.; Fereshteh, M. P.; Ruepp, S.; Palanisamy, K.; Mariappan, T. T.; Maddi, S.; Saxena, A.; Elzinga, P.; Chimalakonda, A.; Ruan, Q.; Ghosh, K.; Bose, S.; Sack, J.; Yan, C.; Kiefer, S. E.; Xie, D.; Newitt, J. A.; Saravanakumar, S. P.; Rampulla, R. A.; Barrish, J. C.; Carter, P. H.; Hynes, J., Jr Optimization of nicotinamides as potent and selective IRAK4 inhibitors with efficacy in a murine model of psoriasis. ACS Med. Chem. Lett. 2020, 11, 1402– 1409, DOI: 10.1021/acsmedchemlett.0c00082[ACS Full Text], [CAS], Google Scholar171https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtFWrtbnE&md5=b69996de3d735163ea72a58e89778a97Optimization of Nicotinamides as Potent and Selective IRAK4 Inhibitors with Efficacy in a Murine Model of PsoriasisNair, Satheesh; Kumar, Sreekantha Ratna; Paidi, Venkatram Reddy; Sistla, Ramesh; Kantheti, Durgarao; Polimera, Subba Rao; Thangavel, Soodamani; Mukherjee, Amrita Jha; Das, Mitalee; Bhide, Rajeev S.; Pitts, William J.; Murugesan, Natesan; Dudhgoankar, Shailesh; Nagar, Jignesh; Subramani, Siva; Mazumder, Debarati; Carman, Julie A.; Holloway, Deborah A.; Li, Xin; Fereshteh, Mark P.; Ruepp, Stefan; Palanisamy, Kamalavenkatesh; Mariappan, T. Thanga; Maddi, Srinivas; Saxena, Ajay; Elzinga, Paul; Chimalakonda, Anjaneya; Ruan, Qian; Ghosh, Kaushik; Bose, Sucharita; Sack, John; Yan, Chunhong; Kiefer, Susan E.; Xie, Dianlin; Newitt, John A.; Saravanakumar, S. Pon; Rampulla, Richard A.; Barrish, Joel C.; Carter, Percy H.; Hynes, JohnACS Medicinal Chemistry Letters (2020), 11 (7), 1402-1409CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)IRAK4 is an attractive therapeutic target for the treatment of inflammatory conditions. Structure guided optimization of a nicotinamide series of inhibitors has been expanded to explore the IRAK4 front pocket. This has resulted in the identification of compds. such as 12 with improved potency and selectivity. Addnl. 12 demonstrated activity in a pharmacokinetics/pharmacodynamics (PK/PD) model. Further optimization efforts led to the identification of the highly kinome selective 21, which demonstrated a robust PD effect and efficacy in a TLR7 driven model of murine psoriasis.
- 172Rajapaksa, N. S.; Gobbi, A.; Drobnick, J.; Do, S.; Kolesnikov, A.; Liang, J.; Chen, Y.; Sujatha-Bhaskar, S.; Huang, Z.; Brightbill, H.; Francis, R.; Yu, C.; Choo, E. F.; DeMent, K.; Ran, Y.; An, L.; Emson, C.; Maher, J.; Wai, J.; McKenzie, B. S.; Lupardus, P. J.; Zarrin, A. A.; Kiefer, J. R.; Bryan, M. C. Discovery of potent benzolactam IRAK4 inhibitors with robust in vivo activity. ACS Med. Chem. Lett. 2020, 11, 327– 333, DOI: 10.1021/acsmedchemlett.9b00380[ACS Full Text], [CAS], Google Scholar172https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitFeqs7%252FJ&md5=2fd1d26eea65c726e463cbb8591303efDiscovery of Potent Benzolactam IRAK4 Inhibitors with Robust in Vivo ActivityRajapaksa, Naomi S.; Gobbi, Alberto; Drobnick, Joy; Do, Steven; Kolesnikov, Aleksandr; Liang, Jun; Chen, Yongsheng; Sujatha-Bhaskar, Swathi; Huang, Zhiyu; Brightbill, Hans; Francis, Ross; Yu, Christine; Choo, Edna F.; De Ment, Kevin; Ran, Yingqing; An, Le; Emson, Claire; Maher, Jonathan; Wai, John; McKenzie, Brent S.; Lupardus, Patrick J.; Zarrin, Ali A.; Kiefer, James R.; Bryan, Marian C.ACS Medicinal Chemistry Letters (2020), 11 (3), 327-333CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)IRAK4 kinase activity transduces signaling from multiple IL-1Rs and TLRs to regulate cytokines and chemokines implicated in inflammatory diseases. As such, there is high interest in identifying selective IRAK4 inhibitors for the treatment of these disorders. We previously reported the discovery of potent and selective dihydrobenzofuran inhibitors of IRAK4. Subsequent studies, however, showed inconsistent inhibition in disease-relevant pharmacodynamic models. Herein, we describe application of a human whole blood assay to the discovery of a series of benzolactam IRAK4 inhibitors. We identified potent mol. 19 which achieves robust in vivo inhibition of cytokines relevant to human disease.
- 173Beurel, E.; Grieco, S. F.; Jope, R. S. Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases. Pharmacol. Ther. 2015, 148, 114– 131, DOI: 10.1016/j.pharmthera.2014.11.016[Crossref], [PubMed], [CAS], Google Scholar173https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVeisr7J&md5=a6c54e0331492b0b61a9d67b1f07575dGlycogen synthase kinase-3 (GSK3): Regulation, actions, and diseasesBeurel, Eleonore; Grieco, Steven F.; Jope, Richard S.Pharmacology & Therapeutics (2015), 148 (), 114-131CODEN: PHTHDT; ISSN:0163-7258. (Elsevier)A review. Glycogen synthase kinase-3 (GSK3) may be the busiest kinase in most cells, with over 100 known substrates to deal with. How does GSK3 maintain control to selectively phosphorylate each substrate, and why was it evolutionarily favorable for GSK3 to assume such a large responsibility. GSK3 must be particularly adaptable for incorporating new substrates into its repertoire, and we discuss the distinct properties of GSK3 that may contribute to its capacity to fulfill its roles in multiple signaling pathways. The mechanisms regulating GSK3 (predominantly post-translational modifications, substrate priming, cellular trafficking, protein complexes) have been reviewed previously, so here we focus on newly identified complexities in these mechanisms, how each of these regulatory mechanism contributes to the ability of GSK3 to select which substrates to phosphorylate, and how these mechanisms may have contributed to its adaptability as new substrates evolved. The current understanding of the mechanisms regulating GSK3 is reviewed, as are emerging topics in the actions of GSK3, particularly its interactions with receptors and receptor-coupled signal transduction events, and differential actions and regulation of the two GSK3 isoforms, GSK3α and GSK3β. Another remarkable characteristic of GSK3 is its involvement in many prevalent disorders, including psychiatric and neurol. diseases, inflammatory diseases, cancer, and others. We address the feasibility of targeting GSK3 therapeutically, and provide an update of its involvement in the etiol. and treatment of several disorders.
- 174Saraswati, A. P.; Ali Hussaini, S. M.; Krishna, N. H.; Babu, B. N.; Kamal, A. Glycogen synthase kinase-3 and its inhibitors: Potential target for various therapeutic conditions. Eur. J. Med. Chem. 2018, 144, 843– 858, DOI: 10.1016/j.ejmech.2017.11.103[Crossref], [PubMed], [CAS], Google Scholar174https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXksFGmsg%253D%253D&md5=f1c93ccbd2546fd13296744079255b51Glycogen synthase kinase-3 and its inhibitors: Potential target for various therapeutic conditionsSaraswati, A. Prasanth; Ali Hussaini, S. M.; Krishna, Namballa Hari; Babu, Bathini Nagendra; Kamal, AhmedEuropean Journal of Medicinal Chemistry (2018), 144 (), 843-858CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)A review. Glycogen Synthase Kinase-3 (GSK-3) is a serine/threonine kinase which is ubiquitously expressed and is regarded as a regulator for various cellular events and signaling pathways. It exists in two isoforms, GSK-3α and GSK-3β and can phosphorylate a wide range of substrates. Aberrancy in the GSK-3 activity can lead to various diseases like Alzheimer's, diabetes, cancer, neurodegeneration etc., rendering it an attractive target to develop potent and specific inhibitors. The present review focuses on the recent developments in the area of GSK-3 inhibitors and also enlightens its therapeutic applicability in various disease conditions.
- 175Zhang, F.; Phiel, C. J.; Spece, L.; Gurvich, N.; Klein, P. S. Inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3) in response to lithium. Evidence for autoregulation of GSK-3. J. Biol. Chem. 2003, 278, 33067– 33077, DOI: 10.1074/jbc.M212635200[Crossref], [PubMed], [CAS], Google Scholar175https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXms1als78%253D&md5=f464ab443eb5186e14ad9a028bc57c45Inhibitory Phosphorylation of Glycogen Synthase Kinase-3 (GSK-3) in Response to Lithium: EVIDENCE FOR AUTOREGULATION OF GSK-3Zhang, Fang; Phiel, Christopher J.; Spece, Laura; Gurvich, Nadia; Klein, Peter S.Journal of Biological Chemistry (2003), 278 (35), 33067-33077CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Glycogen synthase kinase-3 (GSK-3) is a crit., neg. regulator of diverse signaling pathways. Lithium is a direct inhibitor of GSK-3 and has been widely used to test the putative role of GSK-3 in multiple settings. However, lithium also inhibits other targets, including inositol monophosphatase and structurally related phosphomonoesterases, and thus addnl. approaches are needed to attribute a given biol. effect of lithium to a specific target. For example, lithium is known to increase the inhibitory N-terminal phosphorylation of GSK-3, but the target of lithium responsible for this indirect regulation has not been identified. We have characterized a short peptide derived from the GSK-3 interaction domain of Axin that potently inhibits GSK-3 activity in vitro and in mammalian cells and robustly activates Wnt-dependent transcription, mimicking lithium action. We show here, using the GSK-3 interaction domain peptide, as well as small mol. inhibitors of GSK-3, that lithium induces GSK-3 N-terminal phosphorylation through direct inhibition of GSK-3 itself. Redn. of GSK-3 protein levels, either by RNA interference or by disruption of the mouse GSK-3β gene, causes increased N-terminal phosphorylation of GSK-3, confirming that GSK-3 regulates its own phosphorylation status. Finally, evidence is presented that N-terminal phosphorylation of GSK-3 can be regulated by the GSK-3-dependent protein phosphatase-1 inhibitor-2 complex.
- 176Dominguez, J. M.; Fuertes, A.; Orozco, L.; del Monte-Millan, M.; Delgado, E.; Medina, M. Evidence for irreversible inhibition of glycogen synthase kinase-3β by tideglusib. J. Biol. Chem. 2012, 287, 893– 904, DOI: 10.1074/jbc.M111.306472[Crossref], [PubMed], [CAS], Google Scholar176https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjslyquw%253D%253D&md5=abc515bddc24ed0ceac990b2335c3816Evidence for Irreversible Inhibition of Glycogen Synthase Kinase-3β by TideglusibDominguez, Juan Manuel; Fuertes, Ana; Orozco, Leyre; del Monte-Millan, Maria; Delgado, Elena; Medina, MiguelJournal of Biological Chemistry (2012), 287 (2), 893-904CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Tideglusib is a GSK-3 inhibitor currently in phase II clin. trials for the treatment of Alzheimer disease and progressive supranuclear palsy. Sustained oral administration of the compd. to a variety of animal models decreases Tau hyperphosphorylation, lowers brain amyloid plaque load, improves learning and memory, and prevents neuronal loss. We report here that tideglusib inhibits GSK-3β irreversibly, as demonstrated by the lack of recovery in enzyme function after the unbound drug was removed from the reaction medium and the fact that its dissocn. rate const. is non-significantly different from zero. Such irreversibility may explain the non-competitive inhibition pattern with respect to ATP shown by tideglusib and perhaps other structurally related compds. The replacement of Cys-199 by an Ala residue in the enzyme seems to increase the dissocn. rate, although the drug retains its inhibitory activity with decreased potency and long residence time. In addn., tideglusib failed to inhibit a series of kinases that contain a Cys homologous to Cys-199 in their active site, suggesting that its inhibition of GSK-3β obeys to a specific mechanism and is not a consequence of nonspecific reactivity. Results obtained with [35S]tideglusib do not support unequivocally the existence of a covalent bond between the drug and GSK-3β. The irreversibility of the inhibition and the very low protein turnover rate obsd. for the enzyme are particularly relevant from a pharmacol. perspective and could have significant implications on its therapeutic potential.
- 177Luna-Medina, R.; Cortes-Canteli, M.; Sanchez-Galiano, S.; Morales-Garcia, J. A.; Martinez, A.; Santos, A.; Perez-Castillo, A. NP031112, a thiadiazolidinone compound, prevents inflammation and neurodegeneration under excitotoxic conditions: potential therapeutic role in brain disorders. J. Neurosci. 2007, 27, 5766– 5776, DOI: 10.1523/JNEUROSCI.1004-07.2007[Crossref], [PubMed], [CAS], Google Scholar177https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmsVWnsLs%253D&md5=cce5ea34a1c384eb3c3c17416f4ca440NP031112, a thiadiazolidinone compound, prevents inflammation and neurodegeneration under excitotoxic conditions: potential therapeutic role in brain disordersLuna-Medina, Rosario; Cortes-Canteli, Marta; Sanchez-Galiano, Susana; Morales-Garcia, Jose A.; Martinez, Ana; Santos, Angel; Perez-Castillo, AnaJournal of Neuroscience (2007), 27 (21), 5766-5776CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)Inflammation and neurodegeneration coexist in many acute damage and chronic CNS disorders (e.g., stroke, Alzheimer's disease, Parkinson's disease). A well characterized animal model of brain damage involves administration of kainic acid, which causes limbic seizure activity and subsequent neuronal death, esp. in the CA1 and CA3 pyramidal cells and interneurons in the hilus of the hippocampus. Our previous work demonstrated a potent anti-inflammatory and neuroprotective effect of two thiadiazolidinones compds., NP00111 (2,4-dibenzyl-[1,2,4]thiadiazolidine-3,5-dione) and NP01138 (2-ethyl-4-phenyl-[1,2,4]thiadiazolidine-3,5-dione), in primary cultures of cortical neurons, astrocytes, and microglia. Here, we show that injection of NP031112, a more potent thiadiazolidinone deriv., into the rat hippocampus dramatically reduces kainic acid-induced inflammation, as measured by edema formation using T2-weighted magnetic resonance imaging and glial activation and has a neuroprotective effect in the damaged areas of the hippocampus. Last, NP031112-induced neuroprotection, both in vitro and in vivo, was substantially attenuated by cotreatment with GW9662 (2-chloro-5-nitrobenzanilide), a known antagonist of the nuclear receptor peroxisome proliferator-activated receptor γ, suggesting that the effects of NP031112 can be mediated through activation of this receptor. As such, these findings identify NP031112 as a potential therapeutic agent for the treatment of neurodegenerative disorders.
- 178del Ser, T.; Steinwachs, K. C.; Gertz, H. J.; Andres, M. V.; Gomez-Carrillo, B.; Medina, M.; Vericat, J. A.; Redondo, P.; Fleet, D.; Leon, T. Treatment of Alzheimer’s disease with the GSK-3 inhibitor tideglusib: a pilot study. J. Alzheimer's Dis. 2012, 33, 205– 215, DOI: 10.3233/JAD-2012-120805
- 179Tolosa, E.; Litvan, I.; Hoglinger, G. U.; Burn, D.; Lees, A.; Andres, M. V.; Gomez-Carrillo, B.; Leon, T.; Del Ser, T. A phase 2 trial of the GSK-3 inhibitor tideglusib in progressive supranuclear palsy. Mov. Disord. 2014, 29, 470– 478, DOI: 10.1002/mds.25824[Crossref], [PubMed], [CAS], Google Scholar179https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXlvFSmtL8%253D&md5=4b7899d99427a60b8edae580355a740dA phase 2 trial of the GSK-3 inhibitor tideglusib in progressive supranuclear palsyTolosa, Eduardo; Litvan, Irene; Hoeglinger, Guenter U.; Burn, David; Lees, Andrew; Andres, Maria V.; Gomez-Carrillo, Belen; Leon, Teresa; del Ser, TeodoroMovement Disorders (2014), 29 (4), 470-478CODEN: MOVDEA; ISSN:0885-3185. (Wiley-Blackwell)It is believed that glycogen synthase kinase-3 (GSK-3) hyperphosphorylates tau protein in progressive supranuclear palsy (PSP). The Tau Restoration on PSP (TAUROS) study was a double-blind, placebo-controlled, randomized trial to assess the efficacy, safety, and tolerability of tideglusib, a GSK-3 inhibitor, as potential treatment for PSP. The study enrolled 146 PSP patients with mild-to-moderate disease who were randomized to receive once-daily 600 mg tideglusib, 800 mg tideglusib, or placebo (ratio, 2:2:1) administered orally over 52 wk. The primary endpoint was the change from baseline to week 52 on the PSP rating scale. Secondary endpoints were safety and tolerability of tideglusib, changes in motor function (the Timed Up and Go Test), cognition (Dementia Rating Scale-2, Frontal Assessment Battery, verbal fluency), apathy (Starkstein scale), activities of daily living (Schwab and England scale; Unified Parkinson's Disease Rating Scale, part II), quality of life (EuroQol), and Global Clin. Assessment. Brain atrophy on magnetic resonance imaging and several biomarkers in plasma and cerebrospinal fluid also were examd. No significant differences were detected in the primary or secondary endpoints at week 52 between placebo and either dose of tideglusib. Tideglusib was safe, with the exception of some asymptomatic, transient, and reversible transaminase elevations (mainly alanine aminotransferase) in 9% of patients, and diarrhea in 13% of patients. Tideglusib was generally well tolerated but it did not show clin. efficacy in patients with mild-to-moderate PSP. © 2014 International Parkinson and Movement Disorder Society.
- 180Hoglinger, G. U.; Huppertz, H. J.; Wagenpfeil, S.; Andres, M. V.; Belloch, V.; Leon, T.; Del Ser, T. Tideglusib reduces progression of brain atrophy in progressive supranuclear palsy in a randomized trial. Mov. Disord. 2014, 29, 479– 487, DOI: 10.1002/mds.25815[Crossref], [PubMed], [CAS], Google Scholar180https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cvhtFKruw%253D%253D&md5=e8876397f081e9988acb720e6805b06cTideglusib reduces progression of brain atrophy in progressive supranuclear palsy in a randomized trialHoglinger Gunter U; Huppertz Hans-Jurgen; Wagenpfeil Stefan; Andres Maria V; Belloch Vincente; Leon Teresa; Del Ser TeodoroMovement disorders : official journal of the Movement Disorder Society (2014), 29 (4), 479-87 ISSN:.It is believed that glycogen synthase kinase-3 hyperphosphorylates tau protein in progressive supranuclear palsy (PSP). The Tau Restoration on PSP (TAUROS) trial assessed the glycogen synthase kinase-3 inhibitor tideglusib as potential treatment. For the magnetic resonance imaging (MRI) substudy reported here, we assessed the progression of brain atrophy. TAUROS was a multinational, phase 2, double-blind, placebo-controlled trial in patients with mild-to-moderate PSP who were treated with oral tideglusib (600 mg or 800 mg daily) or with placebo for 1 year. A subset of patients underwent baseline and 52-week MRI. Automated, observer-independent, atlas-based, and mask-based volumetry was done on high-resolution, T1-weighted, three-dimensional data. For primary outcomes, progression of atrophy was compared both globally (brain, cerebrum) and regionally (third ventricle, midbrain, pons) between the active and placebo groups (Bonferroni correction). For secondary outcomes, 15 additional brain structures were explored (Benjamini & Yekutieli correction). In total, MRIs from 37 patient were studied (placebo group, N = 9; tideglusib 600 mg group, N = 19; tideglusib 800 mg group, N = 9). The groups compared well in their demographic characteristics. Clinical results showed no effect of tideglusib over placebo. Progression of atrophy was significantly lower in the active group than in the placebo group for the brain (mean ± standard error of the mean: -1.3% ± 1.4% vs. -3.1% ± 2.3%, respectively), cerebrum (-1.3% ± 1.5% vs. -3.2% ± 2.1%, respectively), parietal lobe (-1.6% ± 1.9% vs. -4.1% ± 3.0%, respectively), and occipital lobe (-0.3% ± 1.8% vs. -2.7% ± 3.2%, respectively). A trend toward reduced atrophy also was observed in the frontal lobe, hippocampus, caudate nucleus, midbrain, and brainstem. In patients with PSP, tideglusib reduced the progression of atrophy in the whole brain, particularly in the parietal and occipital lobes.
- 181Neves, V. C.; Babb, R.; Chandrasekaran, D.; Sharpe, P. T. Promotion of natural tooth repair by small molecule GSK3 antagonists. Sci. Rep. 2017, 7, 39654, DOI: 10.1038/srep39654[Crossref], [PubMed], [CAS], Google Scholar181https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXotlemug%253D%253D&md5=e599a377016cd709e89950d6157b1d4aPromotion of natural tooth repair by small molecule GSK3 antagonistsNeves, Vitor C. M.; Babb, Rebecca; Chandrasekaran, Dhivya; Sharpe, Paul T.Scientific Reports (2017), 7 (), 39654CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)The restoration of dentin lost in deep caries lesions in teeth is a routine and common treatment that involves the use of inorg. cements based on calcium or silicon-based mineral aggregates. Such cements remain in the tooth and fail to degrade and thus normal mineral vol. is never completely restored. Here we describe a novel, biol. approach to dentin restoration that stimulates the natural formation of reparative dentin via the mobilisation of resident stem cells in the tooth pulp. Biodegradable, clin.-approved collagen sponges are used to deliver low doses of small mol. glycogen synthase kinase (GSK-3) antagonists that promote the natural processes of reparative dentin formation to completely restore dentin. Since the carrier sponge is degraded over time, dentin replaces the degraded sponge leading to a complete, effective natural repair. This simple, rapid natural tooth repair process could thus potentially provide a new approach to clin. tooth restoration.
- 182Gray, J. E.; Infante, J. R.; Brail, L. H.; Simon, G. R.; Cooksey, J. F.; Jones, S. F.; Farrington, D. L.; Yeo, A.; Jackson, K. A.; Chow, K. H.; Zamek-Gliszczynski, M. J.; Burris, H. A., 3rd A first-in-human phase I dose-escalation, pharmacokinetic, and pharmacodynamic evaluation of intravenous LY2090314, a glycogen synthase kinase 3 inhibitor, administered in combination with pemetrexed and carboplatin. Invest. New Drugs 2015, 33, 1187– 1196, DOI: 10.1007/s10637-015-0278-7[Crossref], [PubMed], [CAS], Google Scholar182https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsFKnsr3P&md5=432e42751491fdd88a53688888d89909A first-in-human phase I dose-escalation, pharmacokinetic, and pharmacodynamic evaluation of intravenous LY2090314, a glycogen synthase kinase 3 inhibitor, administered in combination with pemetrexed and carboplatinGray, Jhanelle E.; Infante, Jeffrey R.; Brail, Les H.; Simon, George R.; Cooksey, Jennifer F.; Jones, Suzanne F.; Farrington, Daphne L.; Yeo, Adeline; Jackson, Kimberley A.; Chow, Kay H.; Zamek-Gliszczynski, Maciej J.; Burris, Howard A., IIIInvestigational New Drugs (2015), 33 (6), 1187-1196CODEN: INNDDK; ISSN:0167-6997. (Springer)LY2090314 (LY) is a glycogen synthase kinase 3 inhibitor with preclin. efficacy in xenograft models when combined with platinum regimens. A first-in-human phase 1 dose-escalation study evaluated the combination of LY with pemetrexed/carboplatin. Forty-one patients with advanced solid tumors received single-dose LY monotherapy lead-in and 37 patients received LY (10-120 mg) plus pemetrexed/carboplatin (500 mg/m2 and 5-6 AUC, resp.) across 8 dose levels every 21 days. Primary objective was max. tolerated dose (MTD) detn.; secondary endpoints included safety, antitumor activity, pharmacokinetics, and beta-catenin pharmacodynamics. MTD of LY with pemetrexed/carboplatin was 40 mg. Eleven dose-limiting toxicities (DLTs) occurred in ten patients. DLTs during LY monotherapy occurred at ≥40 mg: grade 2 visual disturbance (n = 1) and grade 3/4 peri-infusional thoracic pain during or shortly post infusion (n = 4; chest, upper abdominal, and back pain). Ranitidine was added after de-escalation to 80 mg LY to minimize peri-infusional thoracic pain. Following LY with pemetrexed/carboplatin therapy, DLTs included grade 3/4 thrombocytopenia (n = 4) and grade 4 neutropenia (n = 1). Best overall response by RECIST included 5 confirmed partial responses (non-small cell lung cancer [n = 3], mesothelioma, and breast cancer) and 19 patients having stable disease. Systemic LY exposure was approx. linear over dose range studied. Transient upregulation of beta-catenin measured in peripheral blood mononuclear cells (PBMCs) occurred at 40 mg LY. The initial safety profile of LY2090314 was established. MTD LY dose with pemetrexed/carboplatin is 40 mg IV every 3 wk plus ranitidine. Efficacy of LY plus pemetrexed/carboplatin requires confirmation in randomized trials.
- 183Ramurthy, S.; Pfister, K. B.; Boyce, R. S.; Brown, S. P.; Costales, A. Q.; Desai, M. C.; Fang, E.; Levine, B. H.; Ng, S. C.; Nuss, J. M.; Ring, D. B.; Shafer, C. M.; Shu, W.; Subramanian, S.; Wagman, A. S.; Wang, H.; Bussiere, D. E. Discovery and optimization of novel pyridines as highly potent and selective glycogen synthase kinase 3 inhibitors. Bioorg. Med. Chem. Lett. 2020, 30, 126930, DOI: 10.1016/j.bmcl.2019.126930[Crossref], [PubMed], [CAS], Google Scholar183https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXmt1OjsQ%253D%253D&md5=3586fe892d2283a9096a3c205d214e9aDiscovery and optimization of novel pyridines as highly potent and selective glycogen synthase kinase 3 inhibitorsRamurthy, Savithri; Pfister, Keith B.; Boyce, Rustum S.; Brown, Sean P.; Costales, Abran Q.; Desai, Manoj C.; Fang, Eric; Levine, Barry H.; Ng, Simon C.; Nuss, John M.; Ring, David B.; Shafer, Cynthia M.; Shu, Wei; Subramanian, Sharadha; Wagman, Allan S.; Wang, Haixia; Bussiere, Dirksen E.Bioorganic & Medicinal Chemistry Letters (2020), 30 (4), 126930CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Glycogen synthase kinase-3 plays an essential role in multiple biochem. pathways in the cell, particularly in regards to energy regulation. As such, Glycogen synthase kinase-3 is an attractive target for pharmacol. intervention in a variety of disease states, particularly non-insulin dependent diabetes mellitus. However, due to homol. with other crucial kinases, such as the cyclin-dependent protein kinase CDC2, developing compds. that are both potent and selective is challenging. A novel series of derivs. of 5-nitro-N2-(2-(pyridine-2-ylamino)ethyl)pyridine-2,6-diamine were synthesized and potently inhibit glycogen synthase kinase-3 (GSK3). Potency in the low nanomolar range was obtained along with remarkable selectivity. The compds. activate glycogen synthase in insulin receptor-expressing CHO-IR cells and in primary rat hepatocytes, and have acceptable pharmacokinetics and pharmacodynamics to allow for oral dosing. The x-ray co-crystal structure of human GSK3-β in complex with compd. 1-(6-((2-((6-amino-5-nitropyridin-2-yl)amino)ethyl)amino)-2-(2,4-dichlorophenyl)pyridin-3-yl)-4-methylpiperazin-2-one is reported and provides insights into the structural determinants of the series responsible for its potency and selectivity.
- 184Wagman, A. S.; Boyce, R. S.; Brown, S. P.; Fang, E.; Goff, D.; Jansen, J. M.; Le, V. P.; Levine, B. H.; Ng, S. C.; Ni, Z. J.; Nuss, J. M.; Pfister, K. B.; Ramurthy, S.; Renhowe, P. A.; Ring, D. B.; Shu, W.; Subramanian, S.; Zhou, X. A.; Shafer, C. M.; Harrison, S. D.; Johnson, K. W.; Bussiere, D. E. Synthesis, binding mode, and antihyperglycemic activity of potent and selective (5-imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine inhibitors of Glycogen synthase kinase 3. J. Med. Chem. 2017, 60, 8482– 8514, DOI: 10.1021/acs.jmedchem.7b00922[ACS Full Text], [CAS], Google Scholar184https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1alur3O&md5=f3bc1e9efca1545f9bee29e1bba6cc92Synthesis, Binding Mode, and Antihyperglycemic Activity of Potent and Selective (5-Imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine Inhibitors of Glycogen Synthase Kinase 3Wagman, Allan S.; Boyce, Rustum S.; Brown, Sean P.; Fang, Eric; Goff, Dane; Jansen, Johanna M.; Le, Vincent P.; Levine, Barry H.; Ng, Simon C.; Ni, Zhi-Jie; Nuss, John M.; Pfister, Keith B.; Ramurthy, Savithri; Renhowe, Paul A.; Ring, David B.; Shu, Wei; Subramanian, Sharadha; Zhou, Xiaohui A.; Shafer, Cynthia M.; Harrison, Stephen D.; Johnson, Kirk W.; Bussiere, Dirksen E.Journal of Medicinal Chemistry (2017), 60 (20), 8482-8514CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)In an effort to identify new antidiabetic agents, we have discovered a novel family of (5-imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine analogs which are inhibitors of human glycogen synthase kinase 3 (GSK3). We developed efficient synthetic routes to explore a wide variety of substitution patterns and convergently access a diverse array of analogs. Compd. I (CHIR-911, CT-99021, or CHIR-73911) emerged from an exploration of heterocycles at the C-5 position, Ph groups at C-4, and a variety of differently substituted linker and aminopyridine moieties attached at the C-2 position. These compds. exhibited GSK3 IC50s in the low nanomolar range and excellent selectivity. They activate glycogen synthase in insulin receptor-expressing CHO-IR cells and primary rat hepatocytes. Evaluation of lead compds. I and II (CHIR-611 or CT-98014) in rodent models of type 2 diabetes revealed that single oral doses lowered hyperglycemia within 60 min, enhanced insulin-stimulated glucose transport, and improved glucose disposal without increasing insulin levels.
- 185Luo, G.; Chen, L.; Burton, C. R.; Xiao, H.; Sivaprakasam, P.; Krause, C. M.; Cao, Y.; Liu, N.; Lippy, J.; Clarke, W. J.; Snow, K.; Raybon, J.; Arora, V.; Pokross, M.; Kish, K.; Lewis, H. A.; Langley, D. R.; Macor, J. E.; Dubowchik, G. M. Discovery of isonicotinamides as highly selective, brain penetrable, and orally active Glycogen synthase kinase-3 inhibitors. J. Med. Chem. 2016, 59, 1041– 1051, DOI: 10.1021/acs.jmedchem.5b01550[ACS Full Text], [CAS], Google Scholar185https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xmslertg%253D%253D&md5=d0412c3fe9b430c59f861fa10d3eff79Discovery of Isonicotinamides as Highly Selective, Brain Penetrable, and Orally Active Glycogen Synthase Kinase-3 InhibitorsLuo, Guanglin; Chen, Ling; Burton, Catherine R.; Xiao, Hong; Sivaprakasam, Prasanna; Krause, Carol M.; Cao, Yang; Liu, Nengyin; Lippy, Jonathan; Clarke, Wendy J.; Snow, Kimberly; Raybon, Joseph; Arora, Vinod; Pokross, Matt; Kish, Kevin; Lewis, Hal A.; Langley, David R.; Macor, John E.; Dubowchik, Gene M.Journal of Medicinal Chemistry (2016), 59 (3), 1041-1051CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)GSK-3 is a serine/threonine kinase that has numerous substrates. Many of these proteins are involved in the regulation of diverse cellular functions, including metab., differentiation, proliferation, and apoptosis. Inhibition of GSK-3 may be useful in treating a no. of diseases including Alzheimer's disease (AD), type II diabetes, mood disorders, and some cancers, but the approach poses significant challenges. Here, the authors present a class of isonicotinamides, e.g. I [R = F, Cl] that are potent, highly kinase-selective GSK-3 inhibitors, the members of which demonstrated oral activity in a triple-transgenic mouse model of AD. The remarkably high kinase selectivity and straightforward synthesis of these compds. bode well for their further exploration as tool compds. and therapeutics.
- 186Griebel, G.; Stemmelin, J.; Lopez-Grancha, M.; Boulay, D.; Boquet, G.; Slowinski, F.; Pichat, P.; Beeske, S.; Tanaka, S.; Mori, A.; Fujimura, M.; Eguchi, J. The selective GSK3 inhibitor, SAR502250, displays neuroprotective activity and attenuates behavioral impairments in models of neuropsychiatric symptoms of Alzheimer’s disease in rodents. Sci. Rep. 2019, 9, 18045, DOI: 10.1038/s41598-019-54557-5[Crossref], [PubMed], [CAS], Google Scholar186https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlWkur7E&md5=3573c37862802bb661aa83750529be88The selective GSK3 inhibitor, SAR502250, displays neuroprotective activity and attenuates behavioral impairments in models of neuropsychiatric symptoms of Alzheimer's disease in rodentsGriebel, Guy; Stemmelin, Jeanne; Lopez-Grancha, Mati; Boulay, Denis; Boquet, Gerald; Slowinski, Franck; Pichat, Philippe; Beeske, Sandra; Tanaka, Shinji; Mori, Akiko; Fujimura, Masatake; Eguchi, JunichiScientific Reports (2019), 9 (1), 18045CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)Glycogen synthase kinase 3 (GSK3) has been identified as a promising target for the treatment of Alzheimer's disease (AD), where abnormal activation of this enzyme has been assocd. with hyperphosphorylation of tau proteins. This study describes the effects of the selective GSK3 inhibitor, SAR502250, in models of neuroprotection and neuropsychiatric symptoms (NPS) assocd. with AD. In P301L human tau transgenic mice, SAR502250 attenuated tau hyperphosphorylation in the cortex and spinal cord. SAR502250 prevented the increase in neuronal cell death in rat embryonic hippocampal neurons following application of the neurotoxic peptide, Aβ25-35. In behavioral studies, SAR502250 improved the cognitive deficit in aged transgenic APP(SW)/Tau(VLW) mice or in adult mice after infusion of Aβ 25-35. It attenuated aggression in the mouse defense test battery and improved depressive-like state of mice in the chronic mild stress procedure after 4 wk of treatment. Moreover, SAR502250 decreased hyperactivity produced by psychostimulants. In contrast, the drug failed to modify anxiety-related behaviors or sensorimotor gating deficit. This profile confirms the neuroprotective effects of GSK3 inhibitors and suggests an addnl. potential in the treatment of some NPS assocd. with AD.
- 187Liang, S. H.; Chen, J. M.; Normandin, M. D.; Chang, J. S.; Chang, G. C.; Taylor, C. K.; Trapa, P.; Plummer, M. S.; Para, K. S.; Conn, E. L.; Lopresti-Morrow, L.; Lanyon, L. F.; Cook, J. M.; Richter, K. E.; Nolan, C. E.; Schachter, J. B.; Janat, F.; Che, Y.; Shanmugasundaram, V.; Lefker, B. A.; Enerson, B. E.; Livni, E.; Wang, L.; Guehl, N. J.; Patnaik, D.; Wagner, F. F.; Perlis, R.; Holson, E. B.; Haggarty, S. J.; El Fakhri, G.; Kurumbail, R. G.; Vasdev, N. Discovery of a highly selective Glycogen synthase kinase-3 inhibitor (PF-04802367) that modulates tau phosphorylation in the brain: translation for PET neuroimaging. Angew. Chem., Int. Ed. 2016, 55, 9601– 9605, DOI: 10.1002/anie.201603797[Crossref], [PubMed], [CAS], Google Scholar187https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtV2itLbF&md5=83a1bfbe16022e6cc30445c2afbab0a1Discovery of a Highly Selective Glycogen Synthase Kinase-3 Inhibitor (PF-04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET NeuroimagingLiang, Steven H.; Chen, Jinshan Michael; Normandin, Marc D.; Chang, Jeanne S.; Chang, George C.; Taylor, Christine K.; Trapa, Patrick; Plummer, Mark S.; Para, Kimberly S.; Conn, Edward L.; Lopresti-Morrow, Lori; Lanyon, Lorraine F.; Cook, James M.; Richter, Karl E. G.; Nolan, Charlie E.; Schachter, Joel B.; Janat, Fouad; Che, Ye; Shanmugasundaram, Veerabahu; Lefker, Bruce A.; Enerson, Bradley E.; Livni, Elijahu; Wang, Lu; Guehl, Nicolas J.; Patnaik, Debasis; Wagner, Florence F.; Perlis, Roy; Holson, Edward B.; Haggarty, Stephen J.; El Fakhri, Georges; Kurumbail, Ravi G.; Vasdev, NeilAngewandte Chemie, International Edition (2016), 55 (33), 9601-9605CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Glycogen synthase kinase-3 (GSK-3) regulates multiple cellular processes in diabetes, oncol., and neurol. N-(3-(1H-1,2,4-triazol-1-yl)propyl)-5-(3-chloro-4-methoxyphenyl)oxazole-4-carboxamide (PF-04802367 or PF-367) has been identified as a highly potent inhibitor, which is among the most selective antagonists of GSK-3 to date. Its efficacy was demonstrated in modulation of tau phosphorylation in vitro and in vivo. Whereas the kinetics of PF-367 binding in brain tissues are too fast for an effective therapeutic agent, the pharmacokinetic profile of PF-367 is ideal for discovery of radiopharmaceuticals for GSK-3 in the central nervous system. A 11C-isotopologue of PF-367 was synthesized and preliminary PET imaging studies in non-human primates confirmed that we have overcome the two major obstacles for imaging GSK-3, namely, reasonable brain permeability and displaceable binding.
- 188Furlotti, G.; Alisi, M. A.; Cazzolla, N.; Dragone, P.; Durando, L.; Magaro, G.; Mancini, F.; Mangano, G.; Ombrato, R.; Vitiello, M.; Armirotti, A.; Capurro, V.; Lanfranco, M.; Ottonello, G.; Summa, M.; Reggiani, A. Hit optimization of 5-substituted-N-(piperidin-4-ylmethyl)-1H-indazole-3-carboxamides: potent Glycogen synthase kinase-3 (GSK-3) inhibitors with in vivo activity in model of mood disorders. J. Med. Chem. 2015, 58, 8920– 8937, DOI: 10.1021/acs.jmedchem.5b01208[ACS Full Text], [CAS], Google Scholar188https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1OqtLbP&md5=9a62da8ef7a7ca4e4b6ff046c0ba1df6Hit Optimization of 5-Substituted-N-(piperidin-4-ylmethyl)-1H-indazole-3-carboxamides: Potent Glycogen Synthase Kinase-3 (GSK-3) Inhibitors with in Vivo Activity in Model of Mood DisordersFurlotti, Guido; Alisi, Maria Alessandra; Cazzolla, Nicola; Dragone, Patrizia; Durando, Lucia; Magaro, Gabriele; Mancini, Francesca; Mangano, Giorgina; Ombrato, Rosella; Vitiello, Marco; Armirotti, Andrea; Capurro, Valeria; Lanfranco, Massimiliano; Ottonello, Giuliana; Summa, Maria; Reggiani, AngeloJournal of Medicinal Chemistry (2015), 58 (22), 8920-8937CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Novel treatments for bipolar disorder with improved efficacy and broader spectrum of activity are urgently needed. Glycogen synthase kinase 3β (GSK-3β) has been suggested to be a key player in the pathophysiol. of bipolar disorder. A series of novel GSK-3β inhibitors having the common N-[(1-alkylpiperidin-4-yl)methyl]-1H-indazole-3-carboxamide scaffold were prepd. taking advantage of an X-ray cocrystal structure of compd. 5 with GSK-3β. We probed different substitutions at the indazole 5-position and at the piperidine-nitrogen to obtain potent ATP-competitive GSK-3β inhibitors with good cell activity. Among the compds. assessed in the in vivo PK expts., 14i showed, after i.p. dosing, encouraging plasma PK profile and brain exposure, as well as efficacy in a mouse model of mania. Compd. 14i was selected for further in vitro/in vivo pharmacol. evaluation, in order to elucidate the use of ATP-competitive GSK-3β inhibitors as new tools in the development of new treatments for mood disorders.
- 189Palomo, V.; Perez, D. I.; Roca, C.; Anderson, C.; Rodriguez-Muela, N.; Perez, C.; Morales-Garcia, J. A.; Reyes, J. A.; Campillo, N. E.; Perez-Castillo, A. M.; Rubin, L. L.; Timchenko, L.; Gil, C.; Martinez, A. Subtly modulating Glycogen synthase kinase 3β: allosteric inhibitor development and their potential for the treatment of chronic diseases. J. Med. Chem. 2017, 60, 4983– 5001, DOI: 10.1021/acs.jmedchem.7b00395[ACS Full Text], [CAS], Google Scholar189https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXos1SgurY%253D&md5=858ba99deb166b43a488c1141c40ff63Subtly Modulating Glycogen Synthase Kinase 3 β: Allosteric Inhibitor Development and Their Potential for the Treatment of Chronic DiseasesPalomo, Valle; Perez, Daniel I.; Roca, Carlos; Anderson, Cara; Rodriguez-Muela, Natalia; Perez, Concepcion; Morales-Garcia, Jose A.; Reyes, Julio A.; Campillo, Nuria E.; Perez-Castillo, Ana M.; Rubin, Lee L.; Timchenko, Lubov; Gil, Carmen; Martinez, AnaJournal of Medicinal Chemistry (2017), 60 (12), 4983-5001CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Glycogen synthase kinase 3β (GSK-3β) is a central target in several unmet diseases. To increase the specificity of GSK-3β inhibitors in chronic treatments, we developed small mols. allowing subtle modulation of GSK-3β activity. Design synthesis, structure-activity relationships, and binding mode of quinoline-3-carbohydrazide derivs. as allosteric modulators of GSK-3β are presented here. Furthermore, we show how allosteric binders may overcome the β-catenin side effects assocd. with strong GSK-3β inhibition. The therapeutic potential of some of these modulators has been tested in human samples from patients with congenital myotonic dystrophy type 1 (CDM1) and spinal muscular atrophy (SMA) patients. We found that compd. I (R1 = 6-Br, R2 = Et, R3 = C11H23) improves delayed myogenesis in CDM1 myoblasts, while compds. I (R1 = H, 6-Br, R2 = Et, R3 = C11H23) have neuroprotective properties in SMA-derived cells. These findings suggest that the allosteric modulators of GSK-3β may be used for future development of drugs for DM1, SMA, and other chronic diseases where GSK-3β inhibition exhibits therapeutic effects.
- 190Wagner, F. F.; Bishop, J. A.; Gale, J. P.; Shi, X.; Walk, M.; Ketterman, J.; Patnaik, D.; Barker, D.; Walpita, D.; Campbell, A. J.; Nguyen, S.; Lewis, M.; Ross, L.; Weiwer, M.; An, W. F.; Germain, A. R.; Nag, P. P.; Metkar, S.; Kaya, T.; Dandapani, S.; Olson, D. E.; Barbe, A. L.; Lazzaro, F.; Sacher, J. R.; Cheah, J. H.; Fei, D.; Perez, J.; Munoz, B.; Palmer, M.; Stegmaier, K.; Schreiber, S. L.; Scolnick, E.; Zhang, Y. L.; Haggarty, S. J.; Holson, E. B.; Pan, J. Q. Inhibitors of Glycogen synthase kinase 3 with exquisite kinome-wide selectivity and their functional effects. ACS Chem. Biol. 2016, 11, 1952– 1963, DOI: 10.1021/acschembio.6b00306[ACS Full Text], [CAS], Google Scholar190https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFemtr7I&md5=2cfb60c9c1936e5ef9986842aedf473fInhibitors of Glycogen Synthase Kinase 3 with Exquisite Kinome-Wide Selectivity and Their Functional EffectsWagner, Florence F.; Bishop, Joshua A.; Gale, Jennifer P.; Shi, Xi; Walk, Michelle; Ketterman, Joshua; Patnaik, Debasis; Barker, Doug; Walpita, Deepika; Campbell, Arthur J.; Nguyen, Shannon; Lewis, Michael; Ross, Linda; Weiwer, Michel; An, W. Frank; Germain, Andrew R.; Nag, Partha P.; Metkar, Shailesh; Kaya, Taner; Dandapani, Sivaraman; Olson, David E.; Barbe, Anne-Laure; Lazzaro, Fanny; Sacher, Joshua R.; Cheah, Jaime H.; Fei, David; Perez, Jose; Munoz, Benito; Palmer, Michelle; Stegmaier, Kimberly; Schreiber, Stuart L.; Scolnick, Edward; Zhang, Yan-Ling; Haggarty, Stephen J.; Holson, Edward B.; Pan, Jen Q.ACS Chemical Biology (2016), 11 (7), 1952-1963CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)The mood stabilizer lithium, the first-line treatment for bipolar disorder, is hypothesized to exert its effects through direct inhibition of glycogen synthase kinase 3 (GSK3) and indirectly by increasing GSK3's inhibitory serine phosphorylation. GSK3 comprises two highly similar paralogs, GSK3α and GSK3β, which are key regulatory kinases in the canonical Wnt pathway. GSK3 stands as a nodal target within this pathway and is an attractive therapeutic target for multiple indications. Despite being an active field of research for the past 20 years, many GSK3 inhibitors demonstrate either poor to moderate selectivity vs. the broader human kinome or physicochem. properties unsuitable for use in in vitro systems or in vivo models. A nonconventional anal. of data from a GSK3β inhibitor high-throughput screening campaign, which excluded known GSK3 inhibitor chemotypes, led to the discovery of a novel pyrazolo-tetrahydroquinolinone scaffold with unparalleled kinome-wide selectivity for the GSK3 kinases. Taking advantage of an uncommon tridentate interaction with the hinge region of GSK3, we developed highly selective and potent GSK3 inhibitors, BRD1652 and BRD0209, which demonstrated in vivo efficacy in a dopaminergic signaling paradigm modeling mood-related disorders. These new chem. probes open the way for exclusive analyses of the function of GSK3 kinases in multiple signaling pathways involved in many prevalent disorders.
- 191Goldstein, D. M.; Kuglstatter, A.; Lou, Y.; Soth, M. J. Selective p38α inhibitors clinically evaluated for the treatment of chronic inflammatory disorders. J. Med. Chem. 2010, 53, 2345– 2353, DOI: 10.1021/jm9012906[ACS Full Text], [CAS], Google Scholar191https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsV2htb%252FM&md5=6bd2bae9fa21fbb56b3e3600aa460580Selective p38α Inhibitors Clinically Evaluated for the Treatment of Chronic Inflammatory DisordersGoldstein, David M.; Kuglstatter, Andreas; Lou, Yan; Soth, Michael J.Journal of Medicinal Chemistry (2010), 53 (6), 2345-2353CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. This Perspective will summarize key learnings from over 15 years of industrial experience with p38 alpha as a drug target, with a focus on the rational design of highly selective small mol. inhibitors, followed by a discussion of data for examples that have entered into or are recruiting for phase 2 clin. studies. To date, these results have been disappointing. We conclude that p38α inhibition alone is unlikely to be a successful strategy toward treating chronic inflammatory disorders.
- 192Liu, C.; Lin, J.; Wrobleski, S. T.; Lin, S.; Hynes, J.; Wu, H.; Dyckman, A. J.; Li, T.; Wityak, J.; Gillooly, K. M.; Pitt, S.; Shen, D. R.; Zhang, R. F.; McIntyre, K. W.; Salter-Cid, L.; Shuster, D. J.; Zhang, H.; Marathe, P. H.; Doweyko, A. M.; Sack, J. S.; Kiefer, S. E.; Kish, K. F.; Newitt, J. A.; McKinnon, M.; Dodd, J. H.; Barrish, J. C.; Schieven, G. L.; Leftheris, K. Discovery of 4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo[1,2-f][ 1,2,4]triazine-6-carboxamide (BMS-582949), a clinical p38α MAP kinase inhibitor for the treatment of inflammatory diseases. J. Med. Chem. 2010, 53, 6629– 6639, DOI: 10.1021/jm100540x[ACS Full Text], [CAS], Google Scholar192https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtV2ktLjM&md5=265713fe6a3e7af415e7b8ea3359f384Discovery of 4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo[1,2-f][1,2,4]triazine-6-carboxamide (BMS-582949), a Clinical p38α MAP Kinase Inhibitor for the Treatment of Inflammatory DiseasesLiu, Chunjian; Lin, James; Wrobleski, Stephen T.; Lin, Shuqun; Hynes, John, Jr.; Wu, Hong; Dyckman, Alaric J.; Li, Tianle; Wityak, John; Gillooly, Kathleen M.; Pitt, Sidney; Shen, Ding Ren; Zhang, Rosemary F.; McIntyre, Kim W.; Salter-Cid, Luisa; Shuster, David J.; Zhang, Hongjian; Marathe, Punit H.; Doweyko, Arthur M.; Sack, John S.; Kiefer, Susan E.; Kish, Kevin F.; Newitt, John A.; McKinnon, Murray; Dodd, John H.; Barrish, Joel C.; Schieven, Gary L.; Leftheris, KaterinaJournal of Medicinal Chemistry (2010), 53 (18), 6629-6639CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The discovery and characterization of 7k (BMS-582949), a highly selective p38α MAP kinase inhibitor that is currently in phase II clin. trials for the treatment of rheumatoid arthritis, is described. A key to the discovery was the rational substitution of N-cyclopropyl for N-methoxy in 1a, a previously reported clin. candidate p38α inhibitor. Unlike alkyl and other cycloalkyls, the sp2 character of the cyclopropyl group can confer improved H-bonding characteristics to the directly substituted amide NH. Inhibitor 7k is slightly less active than 1a in the p38α enzymic assay but displays a superior pharmacokinetic profile and, as such, was more effective in both the acute murine model of inflammation and pseudoestablished rat AA model. The binding mode of 7k with p38α was confirmed by X-ray crystallog. anal.
- 193Liu, C.; Lin, J.; Hynes, J.; Wu, H.; Wrobleski, S. T.; Lin, S.; Dhar, T. G.; Vrudhula, V. M.; Sun, J. H.; Chao, S.; Zhao, R.; Wang, B.; Chen, B. C.; Everlof, G.; Gesenberg, C.; Zhang, H.; Marathe, P. H.; McIntyre, K. W.; Taylor, T. L.; Gillooly, K.; Shuster, D. J.; McKinnon, M.; Dodd, J. H.; Barrish, J. C.; Schieven, G. L.; Leftheris, K. Discovery of ((4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methylpyrrolo[1,2-f][1,2,4]triazine-6-carbonyl)(propyl)carbamoyloxy)methyl-2-(4-(phosphonooxy)phenyl)acetate (BMS-751324), a clinical prodrug of p38α MAP kinase inhibitor. J. Med. Chem. 2015, 58, 7775– 7784, DOI: 10.1021/acs.jmedchem.5b00839[ACS Full Text], [CAS], Google Scholar193https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVykt77E&md5=b7b3eb068ea20677400bbd81d8881921Discovery of ((4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methylpyrrolo[1,2-f][1,2,4]triazine-6-carbonyl)(propyl)carbamoyloxy)methyl-2-(4-(phosphonooxy)phenyl)acetate (BMS-751324), a Clinical Prodrug of p38α MAP Kinase InhibitorLiu, Chunjian; Lin, James; Hynes, John; Wu, Hong; Wrobleski, Stephen T.; Lin, Shuqun; Dhar, T. G. Murali; Vrudhula, Vivekananda M.; Sun, Jung-Hui; Chao, Sam; Zhao, Rulin; Wang, Bei; Chen, Bang-Chi; Everlof, Gerry; Gesenberg, Christoph; Zhang, Hongjian; Marathe, Punit H.; McIntyre, Kim W.; Taylor, Tracy L.; Gillooly, Kathleen; Shuster, David J.; McKinnon, Murray; Dodd, John H.; Barrish, Joel C.; Schieven, Gary L.; Leftheris, KaterinaJournal of Medicinal Chemistry (2015), 58 (19), 7775-7784CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)In search for prodrugs to address the issue of pH-dependent soly. and exposure assocd. with I (BMS-582949), a previously disclosed phase II clin. p38α MAP kinase inhibitor, a structurally novel clin. prodrug, II (BMS-751324), featuring a carbamoylmethylene linked promoiety contg. hydroxyphenyl acetic acid (HPA) derived ester and phosphate functionalities, was identified. Prodrug II was not only stable but also water-sol. under both acidic and neutral conditions. It was effectively bioconverted into parent drug I in vivo by alk. phosphatase and esterase in a stepwise manner, providing higher exposure of I compared to its direct administration, esp. within higher dose ranges. In a rat LPS-induced TNFα pharmacodynamic model and a rat adjuvant arthritis model, II demonstrated similar efficacy to I. Most importantly, it was shown in clin. studies that prodrug II was indeed effective in addressing the pH-dependent absorption issue assocd. with I.
- 194Roy, S. M.; Minasov, G.; Arancio, O.; Chico, L. W.; Van Eldik, L. J.; Anderson, W. F.; Pelletier, J. C.; Watterson, D. M. A selective and brain penetrant p38αMAPK inhibitor candidate for neurologic and neuropsychiatric disorders that attenuates neuroinflammation and cognitive dysfunction. J. Med. Chem. 2019, 62, 5298– 5311, DOI: 10.1021/acs.jmedchem.9b00058[ACS Full Text], [CAS], Google Scholar194https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXntleisLs%253D&md5=501c82424ff421416e71b281f7504e21A Selective and Brain Penetrant p38αMAPK Inhibitor Candidate for Neurologic and Neuropsychiatric Disorders That Attenuates Neuroinflammation and Cognitive DysfunctionRoy, Saktimayee M.; Minasov, George; Arancio, Ottavio; Chico, Laura W.; Van Eldik, Linda J.; Anderson, Wayne F.; Pelletier, Jeffrey C.; Watterson, D. MartinJournal of Medicinal Chemistry (2019), 62 (11), 5298-5311CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The p38αMAPK is a serine/threonine protein kinase and a key node in the intracellular signaling networks that transduce and amplify stress signals into physiol. changes. A preponderance of preclin. data and clin. observations established p38αMAPK as a brain drug discovery target involved in neuroinflammatory responses and synaptic dysfunction in multiple degenerative and neuropsychiatric brain disorders. We summarize the discovery of highly selective, brain-penetrant, small mol. p38αMAPK inhibitors that are efficacious in diverse animal models of neurol. disorders. A crystallog. and pharmacoinformatic approach to fragment expansion enabled the discovery of an efficacious hit. The addn. of secondary pharmacol. screens to refinement delivered lead compds. with improved selectivity, appropriate pharmacodynamics, and efficacy. Safety considerations and addnl. secondary pharmacol. screens drove optimization that delivered the drug candidate MW01-18-150SRM (MW150), currently in early stage clin. trials.
- 195Moens, U.; Kostenko, S.; Sveinbjornsson, B. The role of Mitogen-activated protein kinase-activated protein kinases (MAPKAPKs) in inflammation. Genes 2013, 4, 101– 133, DOI: 10.3390/genes4020101[Crossref], [PubMed], [CAS], Google Scholar195https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXmtlGrt7s%253D&md5=3166c5885677dcb50f40bcfa4c37fd3bThe role of mitogen-activated protein kinase-activated protein kinases (MAPKAPKs) in inflammationMoens, Ugo; Kostenko, Sergiy; Sveinbjoernsson, BaldurGenes (2013), 4 (2), 101-133, 33 pp.CODEN: GENEG9; ISSN:2073-4425. (MDPI AG)A review. Mitogen-activated protein kinase (MAPK) pathways are implicated in several cellular processes including proliferation, differentiation, apoptosis, cell survival, cell motility, metab., stress response and inflammation. MAPK pathways transmit and convert a plethora of extracellular signals by three consecutive phosphorylation events involving a MAPK kinase kinase, a MAPK kinase and a MAPK. In turn MAPKs phosphorylate substrates, including other protein kinases referred to as MAPK-activated protein kinases (MAPKAPKs). Eleven mammalian MAPKAPKs have been identified: ribosomal-S6-kinases (RSK1-4), mitogen- and stress-activated kinases (MSK1-2), MAPK-interacting kinases (MNK1-2), MAPKAPK-2 (MK2), MAPKAPK-3 (MK3) and MAPKAPK-5 (MK5). The role of these MAPKAPKs in inflammation will be reviewed.
- 196Gaestel, M. What goes up must come down: molecular basis of MAPKAP kinase 2/3-dependent regulation of the inflammatory response and its inhibition. Biol. Chem. 2013, 394, 1301– 1315, DOI: 10.1515/hsz-2013-0197[Crossref], [PubMed], [CAS], Google Scholar196https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXlvFent7s%253D&md5=76b71ea718a39f3d007aba58e38ce106What goes up must come down: molecular basis of MAPKAP kinase 2/3-dependent regulation of the inflammatory response and its inhibitionGaestel, MatthiasBiological Chemistry (2013), 394 (10), 1301-1315CODEN: BICHF3; ISSN:1431-6730. (Walter de Gruyter GmbH)A review. Inflammation is normally a fast and transient response to microbial invaders or sterile damage and has to be stringently controlled. The closely-related mitogen-activated protein kinase-activated protein kinases MK2 and MK3 are involved in both up- and down-regulation of inflammation in mammals and govern the inflammatory response at different regulatory levels of gene expression and with different kinetics. In conjunction with their activator MAP kinase p38, MK2 and MK3 stimulate the transcription of immediate-early genes including that of the mRNA-binding protein tristetraprolin (TTP). TTP competes with the constitutively expressed protein human antigen R in binding to the mRNA destabilizing adenylate-uridylate -rich element. MK2 and MK3 also regulate the activity of TTP by direct phosphorylation, det. stability and stimulate the translation of cytokine mRNAs. In addn., TTP controls its own re-synthesis via stability and translation of its mRNA in a phosphorylation-dependent manner. This results in a complex scenario of gene expression and guarantees fast up-regulation and intrinsic feedback control of the inflammatory response of macrophages. Inhibition of MK2/3 by small-mol. pharmaceutical inhibitors is an emerging strategy to manipulate the inflammatory response as a therapeutic option. This strategy could display advantages over the direct inhibition of MAP kinase p38.
- 197Fiore, M.; Forli, S.; Manetti, F. Targeting Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2, MK2): medicinal chemistry efforts to lead small molecule inhibitors to clinical trials. J. Med. Chem. 2016, 59, 3609– 3634, DOI: 10.1021/acs.jmedchem.5b01457[ACS Full Text], [CAS], Google Scholar197https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslWlt7rJ&md5=e6cf6b421991135eddd42154f37c3af1Targeting Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAPK2, MK2): Medicinal Chemistry Efforts To Lead Small Molecule Inhibitors to Clinical TrialsFiore, Mario; Forli, Stefano; Manetti, FabrizioJournal of Medicinal Chemistry (2016), 59 (8), 3609-3634CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The p38/MAPK-activated kinase 2 (MK2) pathway is involved in a series of pathol. conditions (inflammation diseases and metastasis) and in the resistance mechanism to antitumor agents. None of the p38 inhibitors entered advanced clin. trials because of their unwanted systemic side effects. For this reason, MK2 was identified as an alternative target to block the pathway but avoiding the side effects of p38 inhibition. However, ATP-competitive MK2 inhibitors suffered from low soly., poor cell permeability, and scarce kinase selectivity. Fortunately, non-ATP-competitive inhibitors of MK2 have been already discovered that allowed circumventing the selectivity issue. These compds. showed the addnl. advantage to be effective at lower concns. in comparison to the ATP-competitive inhibitors. Therefore, although the significant difficulties encountered during the development of these inhibitors, MK2 is still considered as an attractive target to treat inflammation and related diseases to prevent tumor metastasis and to increase tumor sensitivity to chemotherapeutics.
- 198Singh, R. K.; Najmi, A. K. Novel therapeutic potential of Mitogen-activated protein kinase activated protein kinase 2 (MK2) in chronic airway inflammatory disorders. Curr. Drug Targets 2019, 20, 367– 379, DOI: 10.2174/1389450119666180816121323[Crossref], [PubMed], [CAS], Google Scholar198https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisVCrsr8%253D&md5=4d591506737d6ca4033afd2947f5ab57Novel Therapeutic Potential of Mitogen-Activated Protein Kinase Activated Protein Kinase 2 (MK2) in Chronic Airway Inflammatory DisordersSingh, Rakesh Kumar; Najmi, Abul KalamCurrent Drug Targets (2019), 20 (4), 367-379CODEN: CDTUAU; ISSN:1389-4501. (Bentham Science Publishers Ltd.)Objective: The primary focus of this review is to highlight the current and emerging proinflammatory role of MK2 kinase signaling in p38MAPK pathway and to provide a detailed evaluation on the prospects of MK2 inhibition with special emphasis on the etiol. of chronic inflammatory airway diseases, such as asthma, idiopathic pulmonary fibrosis, lung cancer, acute lung injury and acute respiratory distress syndrome. Background: MK2 belongs to serine-threonine kinase family and is activated directly by stress and inflammatory signal through p38MAPK phosphorylation in diverse inflammatory conditions through the Toll-like receptor signaling pathway. MK2 has been thought to be a crit. factor involved in the regulation of synthesis and release of pro-inflammatory (TNF-α, IL-6 and IL-1β, etc.) proteins. Targeted inhibition of MK2 kinase has been shown to significantly reduce the prodn. and release of these cytokine mols. Therefore, MK2 has been identified as an effective strategy (alternative to p38MAPK) to block this pro-inflammatory signaling pathway. Results: The inhibition of MK2 may lead to similar or better efficacy as that of p38 inhibitors, and interestingly avoids the systemic toxicity shown by the p38 inhibitors. Thus, MK2 has been the focus of intense interdisciplinary research and its specific inhibition can be a novel and potential therapeutic strategy for the treatment of chronic airway inflammatory diseases. Conclusion: Promising advancement in understanding and rigorous exploration of the role of MK2 kinase in inflammatory processes may contribute to the development of newer and safer therapy for the treatment of chronic airway inflammatory diseases in the future.
- 199Mourey, R. J.; Burnette, B. L.; Brustkern, S. J.; Daniels, J. S.; Hirsch, J. L.; Hood, W. F.; Meyers, M. J.; Mnich, S. J.; Pierce, B. S.; Saabye, M. J.; Schindler, J. F.; South, S. A.; Webb, E. G.; Zhang, J.; Anderson, D. R. A benzothiophene inhibitor of mitogen-activated protein kinase-activated protein kinase 2 inhibits tumor necrosis factor α production and has oral anti-inflammatory efficacy in acute and chronic models of inflammation. J. Pharmacol. Exp. Ther. 2010, 333, 797– 807, DOI: 10.1124/jpet.110.166173[Crossref], [PubMed], [CAS], Google Scholar199https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmvFClsLg%253D&md5=312670776fbb3fd39fc2247eba48eb6eA benzothiophene inhibitor of mitogen-activated protein kinase-activated protein kinase 2 inhibits tumor necrosis factor α production and has oral anti-inflammatory efficacy in acute and chronic models of inflammationMourey, Robert J.; Burnette, Barry L.; Brustkern, Sarah J.; Daniels, J. Scott; Hirsch, Jeffrey L.; Hood, William F.; Meyers, Marvin J.; Mnich, Stephen J.; Pierce, Betsy S.; Saabye, Matthew J.; Schindler, John F.; South, Sarah A.; Webb, Elizabeth G.; Zhang, Jian; Anderson, David R.Journal of Pharmacology and Experimental Therapeutics (2010), 333 (3), 797-807CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)Activation of the p38 kinase pathway in immune cells leads to the transcriptional and translational regulation of proinflammatory cytokines. Mitogen-activated protein kinase-activated protein kinase 2 (MK2), a direct downstream substrate of p38 kinase, regulates lipopolysaccharide (LPS)-stimulated tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) prodn. through modulating the stability and translation of these mRNAs. Developing small-mol. inhibitors of MK2 may yield anti-inflammatory efficacy with a different safety profile relative to p38 kinase inhibitors. This article describes the pharmacol. properties of a benzothiophene MK2 inhibitor, PF-3644022 [(10R)-10-methyl-3-(6-methylpyridin-3-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one]. PF-3644022 is a potent freely reversible ATP-competitive compd. that inhibits MK2 activity (Ki = 3 nM) with good selectivity when profiled against 200 human kinases. In the human U937 monocytic cell line or peripheral blood mononuclear cells, PF-3644022 potently inhibits TNFα prodn. with similar activity (IC50 = 160 nM). PF-3644022 blocks TNFα and IL-6 prodn. in LPS-stimulated human whole blood with IC50 values of 1.6 and 10.3 μM, resp. Inhibition of TNFα in U937 cells and blood correlates closely with inhibition of phospho-heat shock protein 27, a target biomarker of MK2 activity. PF-3644022 displays good pharmacokinetic parameters in rats and is orally efficacious in both the rat acute LPS-induced TNFα model and the chronic streptococcal cell wall-induced arthritis model. Dose-dependent inhibition of TNFα prodn. in the acute model and inhibition of paw swelling in the chronic model is obsd. with ED50 values of 6.9 and 20 mg/kg, resp. PF-3644022 efficacy in the chronic inflammation model is strongly correlated with maintaining a Cmin higher than the EC50 measured in the rat LPS-induced TNFα model.
- 200Kosugi, T.; Mitchell, D. R.; Fujino, A.; Imai, M.; Kambe, M.; Kobayashi, S.; Makino, H.; Matsueda, Y.; Oue, Y.; Komatsu, K.; Imaizumi, K.; Sakai, Y.; Sugiura, S.; Takenouchi, O.; Unoki, G.; Yamakoshi, Y.; Cunliffe, V.; Frearson, J.; Gordon, R.; Harris, C. J.; Kalloo-Hosein, H.; Le, J.; Patel, G.; Simpson, D. J.; Sherborne, B.; Thomas, P. S.; Suzuki, N.; Takimoto-Kamimura, M.; Kataoka, K. Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2) as an antiinflammatory target: discovery and in vivo activity of selective pyrazolo[1,5-a]pyrimidine inhibitors using a focused library and structure-based optimization approach. J. Med. Chem. 2012, 55, 6700– 6715, DOI: 10.1021/jm300411k[ACS Full Text], [CAS], Google Scholar200https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpsV2gs7k%253D&md5=78a9e895c0f7a058407de9e344a75458Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAP-K2) as an Antiinflammatory Target: Discovery and in Vivo Activity of Selective Pyrazolo[1,5-a]pyrimidine Inhibitors Using a Focused Library and Structure-Based Optimization ApproachKosugi, Tomomi; Mitchell, Dale R.; Fujino, Aiko; Imai, Minoru; Kambe, Mika; Kobayashi, Shinji; Makino, Hiroaki; Matsueda, Yohei; Oue, Yasuhiro; Komatsu, Kanji; Imaizumi, Keiichiro; Sakai, Yuri; Sugiura, Satoshi; Takenouchi, Osami; Unoki, Gen; Yamakoshi, Yuko; Cunliffe, Vicky; Frearson, Julie; Gordon, Richard; Harris, C. John; Kalloo-Hosein, Heidi; Le, Joelle; Patel, Gita; Simpson, Donald J.; Sherborne, Brad; Thomas, Peter S.; Suzuki, Naotaka; Takimoto-Kamimura, Midori; Kataoka, Ken-ichiroJournal of Medicinal Chemistry (2012), 55 (15), 6700-6715CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A novel class of mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2) inhibitors was discovered through screening a kinase-focused library. A homol. model of MAPKAP-K2 was generated and used to guide the initial SAR studies and to rationalize the obsd. selectivity over CDK2. An x-ray crystal structure of a compd. from the active series bound to cryst. MAPKAP-K2 confirmed the predicted binding mode. This has enabled the discovery of a series of pyrazolo[1,5-a]pyrimidine derivs. showing good in vitro cellular 000 0 potency as anti-TNF-α agents and in vivo efficacy in a mouse model of endotoxin shock.
- 201Velcicky, J.; Schlapbach, A.; Heng, R.; Revesz, L.; Pflieger, D.; Blum, E.; Hawtin, S.; Huppertz, C.; Feifel, R.; Hersperger, R. Modulating ADME properties by fluorination: MK2 inhibitors with improved oral exposure. ACS Med. Chem. Lett. 2018, 9, 392– 396, DOI: 10.1021/acsmedchemlett.8b00098[ACS Full Text], [CAS], Google Scholar201https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXltV2jsLY%253D&md5=6dca69f60838d59b87c90a936682b13aModulating ADME Properties by Fluorination: MK2 Inhibitors with Improved Oral ExposureVelcicky, Juraj; Schlapbach, Achim; Heng, Richard; Revesz, Laszlo; Pflieger, Daniel; Blum, Ernst; Hawtin, Stuart; Huppertz, Christine; Feifel, Roland; Hersperger, ReneACS Medicinal Chemistry Letters (2018), 9 (4), 392-396CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)MAP-activated protein kinase 2 (MK2) plays an important role in the regulation of innate immune response as well as in cell survival upon DNA damage. Despite its potential for the treatment of inflammation and cancer, to date no MK2 low mol. wt. inhibitors have reached the clinic, mainly due to inadequate absorption, distribution, metab., and excretion (ADME) properties. We describe here an approach based on specifically placed fluorine within a recently described pyrrole-based MK2 inhibitor scaffold for manipulation of its physicochem. and ADME properties. While preserving target potency, the novel fluoro-derivs. showed greatly improved permeability as well as enhanced soly. and reduced in vivo clearance leading to significantly increased oral exposure.
- 202Huang, X.; Zhu, X.; Chen, X.; Zhou, W.; Xiao, D.; Degrado, S.; Aslanian, R.; Fossetta, J.; Lundell, D.; Tian, F.; Trivedi, P.; Palani, A. A three-step protocol for lead optimization: quick identification of key conformational features and functional groups in the SAR studies of non-ATP competitive MK2 (MAPKAPK2) inhibitors. Bioorg. Med. Chem. Lett. 2012, 22, 65– 70, DOI: 10.1016/j.bmcl.2011.11.074[Crossref], [PubMed], [CAS], Google Scholar202https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XivVyquw%253D%253D&md5=da2ff998ada081c76f2e9e251af7e109A three-step protocol for lead optimization: Quick identification of key conformational features and functional groups in the SAR studies of non-ATP competitive MK2 (MAPKAPK2) inhibitorsHuang, Xianhai; Zhu, Xiaohong; Chen, Xiao; Zhou, Wei; Xiao, Dong; Degrado, Sylvia; Aslanian, Robert; Fossetta, James; Lundell, Daniel; Tian, Fang; Trivedi, Prashant; Palani, AnandanBioorganic & Medicinal Chemistry Letters (2012), 22 (1), 65-70CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A three-step protocol for SAR development was introduced and applied to the SAR studies of the MK2 inhibitor program. Following this protocol, key conformational features and functional groups for improving MK2 inhibitor activity were quickly identified. Through this effort, the initial gap obsd. between in vitro binding activity and cellular activity in the lead identification stage was very much reduced. Compd. 28 was identified with single digit binding activity (IC50 = 8 nM) and good cellular activity (EC50 = 310 nM). This provides further evidence that non-ATP-competitive binding MK2 inhibitors are feasible by targeting the outside ATP pocket.
- 203Rao, A. U.; Xiao, D.; Huang, X.; Zhou, W.; Fossetta, J.; Lundell, D.; Tian, F.; Trivedi, P.; Aslanian, R.; Palani, A. Facile synthesis of tetracyclic azepine and oxazocine derivatives and their potential as MAPKAP-K2 (MK2) inhibitors. Bioorg. Med. Chem. Lett. 2012, 22, 1068– 1072, DOI: 10.1016/j.bmcl.2011.11.113[Crossref], [PubMed], [CAS], Google Scholar203https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpsFantA%253D%253D&md5=f57cd64420c8735d0f60ad85bdee0b58Facile synthesis of tetracyclic azepine and oxazocine derivatives and their potential as MAPKAP-K2 (MK2) inhibitorsRao, Ashwin U.; Xiao, Dong; Huang, Xianhai; Zhou, Wei; Fossetta, James; Lundell, Dan; Tian, Fang; Trivedi, Prashant; Aslanian, Robert; Palani, AnandanBioorganic & Medicinal Chemistry Letters (2012), 22 (2), 1068-1072CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Facile synthesis of two new series of tetracyclic azepine and oxazocine analogs is described. These analogs were evaluated for their potential as MAPKAP-K2 (MK2) inhibitors and several, e.g., I and II, were found to be potent at inhibiting MK2 with a non-ATP competitive binding mode.
- 204Huang, E. J.; Reichardt, L. F. Trk receptors: roles in neuronal signal transduction. Annu. Rev. Biochem. 2003, 72, 609– 642, DOI: 10.1146/annurev.biochem.72.121801.161629[Crossref], [PubMed], [CAS], Google Scholar204https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXntFSgtbo%253D&md5=939bf60802da0a203c2e0d8585e28dd9Trk receptors: roles in neuronal signal transductionHuang, Eric J.; Reichardt, Louis F.Annual Review of Biochemistry (2003), 72 (), 609-642CODEN: ARBOAW; ISSN:0066-4154. (Annual Reviews Inc.)A review. Trk receptors are a family of 3 receptor tyrosine kinases, each of which can be activated by ≥1 of 4 neurotrophins-nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophins 3 and 4 (NT3 and NT4). Neurotrophin signaling through these receptors regulates cell survival, proliferation, the fate of neural precursors, axon and dendrite growth and patterning, and the expression and activity of functionally important proteins, such as ion channels and neurotransmitter receptors. In the adult nervous system, the Trk receptors regulate synaptic strength and plasticity. The cytoplasmic domains of Trk receptors contain several sites of tyrosine phosphorylation that recruit intermediates in intracellular signaling cascades. As a result, Trk receptor signaling activates several small G proteins, including Ras, Rap-1, and the Cdc-42-Rac-Rho family, as well as pathways regulated by MAP kinase, PI 3-kinase and phospholipase-C-γ (PLC-γ). Trk receptor activation has different consequences in different cells, and the specificity of downstream Trk receptor-mediated signaling is controlled through expression of intermediates in these signaling pathways and membrane trafficking that regulates localization of different signaling constituents. Perhaps the most fascinating aspect of Trk receptor-mediated signaling is its interplay with signaling promoted by the pan-neurotrophin receptor p75NTR. P75NTR activates a distinct set of signaling pathways within cells that are in some instances synergistic and in other instances antagonistic to those activated by Trk receptors. Several of these are proapoptotic but are suppressed by Trk receptor-initiated signaling. P75NTR also influences the conformations of Trk receptors; this modifies ligand-binding specificity and affinity with important developmental consequences.
- 205Yan, W.; Lakkaniga, N. R.; Carlomagno, F.; Santoro, M.; McDonald, N. Q.; Lv, F.; Gunaganti, N.; Frett, B.; Li, H. Y. Insights into current tropomyosin receptor kinase (TRK) inhibitors: development and clinical application. J. Med. Chem. 2019, 62, 1731– 1760, DOI: 10.1021/acs.jmedchem.8b01092[ACS Full Text], [CAS], Google Scholar205https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhs1Khur%252FO&md5=5ce2f8d295cf46f84b46f5890dad0160Insights into Current Tropomyosin Receptor Kinase (TRK) Inhibitors: Development and Clinical ApplicationYan, Wei; Lakkaniga, Naga Rajiv; Carlomagno, Francesca; Santoro, Massimo; McDonald, Neil Q.; Lv, Fengping; Gunaganti, Naresh; Frett, Brendan; Li, Hong-yuJournal of Medicinal Chemistry (2019), 62 (4), 1731-1760CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The use of kinase-directed precision medicine has been heavily pursued since the discovery and development of imatinib. Annually, it is estd. that around ∼20 000 new cases of tropomyosin receptor kinase (TRK) cancers are diagnosed, with the majority of cases exhibiting a TRK genomic rearrangement. In this Perspective, we discuss current development and clin. applications for TRK precision medicine by providing the following: (1) the biol. background and significance of the TRK kinase family, (2) a compilation of known TRK inhibitors and anal. of their cocrystal structures, (3) an overview of TRK clin. trials, and (4) future perspectives for drug discovery and development of TRK inhibitors.
- 206Skerratt, S. E.; Andrews, M.; Bagal, S. K.; Bilsland, J.; Brown, D.; Bungay, P. J.; Cole, S.; Gibson, K. R.; Jones, R.; Morao, I.; Nedderman, A.; Omoto, K.; Robinson, C.; Ryckmans, T.; Skinner, K.; Stupple, P.; Waldron, G. The discovery of a potent, selective, and peripherally restricted pan-Trk inhibitor (PF-06273340) for the treatment of pain. J. Med. Chem. 2016, 59, 10084– 10099, DOI: 10.1021/acs.jmedchem.6b00850[ACS Full Text], [CAS], Google Scholar206https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslWjsbfL&md5=f8c904a92c1716062c217fefe2374ce6The Discovery of a Potent, Selective, and Peripherally Restricted Pan-Trk Inhibitor (PF-06273340) for the Treatment of PainSkerratt, Sarah E.; Andrews, Mark; Bagal, Sharan K.; Bilsland, James; Brown, David; Bungay, Peter J.; Cole, Susan; Gibson, Karl R.; Jones, Russell; Morao, Inaki; Nedderman, Angus; Omoto, Kiyoyuki; Robinson, Colin; Ryckmans, Thomas; Skinner, Kimberly; Stupple, Paul; Waldron, GarethJournal of Medicinal Chemistry (2016), 59 (22), 10084-10099CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The neurotrophin family of growth factors, comprised of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) and neurotrophin 4 (NT4), is implicated in the physiol. of chronic pain. Given the clin. efficacy of anti-NGF monoclonal antibody (mAb) therapies, there is significant interest in the development of small mol. modulators of neurotrophin activity. Neurotrophins signal through the tropomyosin related kinase (Trk) family of tyrosine kinase receptors, hence Trk kinase inhibition represents a potentially "druggable" point of intervention. To deliver the safety profile required for chronic, non-life threatening pain indications, highly kinase-selective Trk inhibitors with minimal brain availability are sought. Herein the authors describe how the use of SBDD, 2D QSAR models and Matched Mol. Pair data in compd. design enabled the delivery of the highly potent, kinase-selective and peripherally restricted clin. candidate PF-06273340.
- 207Loudon, P.; Siebenga, P.; Gorman, D.; Gore, K.; Dua, P.; van Amerongen, G.; Hay, J. L.; Groeneveld, G. J.; Butt, R. P. Demonstration of an anti-hyperalgesic effect of a novel pan-Trk inhibitor PF-06273340 in a battery of human evoked pain models. Br. J. Clin. Pharmacol. 2018, 84, 301– 309, DOI: 10.1111/bcp.13448[Crossref], [PubMed], [CAS], Google Scholar207https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhs1Ois7s%253D&md5=9eeed9ba7e290cf9c3537f30ecd2dc03Demonstration of an anti-hyperalgesic effect of a novel pan-Trk inhibitor PF-06273340 in a battery of human evoked pain modelsLoudon, Peter; Siebenga, Pieter; Gorman, Donal; Gore, Katrina; Dua, Pinky; van Amerongen, Guido; Hay, Justin L.; Groeneveld, Geert Jan; Butt, Richard P.British Journal of Clinical Pharmacology (2018), 84 (2), 301-309CODEN: BCPHBM; ISSN:1365-2125. (Wiley-Blackwell)Inhibitors of nerve growth factor (NGF) reduce pain in several chronic pain indications. NGF signals through tyrosine kinase receptors of the tropomyosin-related kinase (Trk) family and the unrelated p75 receptor. PF-06273340 is a small mol. inhibitor of Trks A, B and C that reduces pain in nonclin. models, and the present study aimed to investigate the pharmacodynamics of this first-in-class mol. in humans. A randomized, double-blind, single-dose, placebo- and active-controlled five-period crossover study was conducted in healthy human subjects (NCT02260947). Subjects received five treatments: PF-06273340 50 mg, PF-06273340 400 mg, pregabalin 300 mg, ibuprofen 600 mg and placebo. The five primary endpoints were the pain detection threshold for the thermal pain tests and the pain tolerance threshold for the cold pressor, elec. stair and pressure pain tests. The trial had predefined decision rules based on 95% confidence that the PF-06273340 effect was better than that of placebo. Twenty subjects entered the study, with 18 completing all five periods. The high dose of PF-06273340 met the decision rules on the UV B skin thermal pain endpoint [least squares (LS) mean vs. placebo: 1.13, 95% confidence interval: 0.64-1.61], but not on the other four primary endpoints. The low dose did not meet the decision criteria for any of the five primary endpoints. Pregabalin (cold pressor and elec. stair tests) and ibuprofen (UVB thermal pain) showed significant analgesic effects on expected endpoints. The study demonstrated, for the first time, the translation of nonclin. effects into man in an inflammatory pain analgesic pharmacodynamic endpoint using a pan-Trk inhibitor.
- 208Wang, T.; Yu, D.; Lamb, M. L. Trk kinase inhibitors as new treatments for cancer and pain. Expert Opin. Ther. Pat. 2009, 19, 305– 319, DOI: 10.1517/13543770902721261[Crossref], [PubMed], [CAS], Google Scholar208https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjslWlu7o%253D&md5=ffc2d3e33102631cac7b89dce7f96a5aTrk kinase inhibitors as new treatments for cancer and painWang, Tao; Yu, Dingwei; Lamb, Michelle L.Expert Opinion on Therapeutic Patents (2009), 19 (3), 305-319CODEN: EOTPEG; ISSN:1354-3776. (Informa Healthcare)A review. Background: Tropomyosin-related kinases (Trks) are a family of receptor tyrosine kinases activated by neurotrophins. Trks play important roles in pain sensation as well as tumor cell growth and survival signaling. Thus, inhibitors of Trk receptor kinases might provide targeted treatments for pain and cancer. Objective: This paper reviews those patent applications since 2002 claiming small-mol. inhibitors of Trk receptor kinases. Methods: Primary literature and patents were searched with SciFinder and Google Scholar. Patents were selected based on their relevance to Trks and were evaluated and representative compds. were listed as examples. Results/conclusion: Several series of Trk inhibitors with excellent in vitro potencies have been reported and a no. of compds. have gone into the clinic. It should be noted that few of these inhibitors are Trk selective, demonstrating that targeting Trk kinases for treatment of pain and/or cancer offers a promising but also challenging approach.
- 209Bagal, S. K.; Andrews, M.; Bechle, B. M.; Bian, J.; Bilsland, J.; Blakemore, D. C.; Braganza, J. F.; Bungay, P. J.; Corbett, M. S.; Cronin, C. N.; Cui, J. J.; Dias, R.; Flanagan, N. J.; Greasley, S. E.; Grimley, R.; James, K.; Johnson, E.; Kitching, L.; Kraus, M. L.; McAlpine, I.; Nagata, A.; Ninkovic, S.; Omoto, K.; Scales, S.; Skerratt, S. E.; Sun, J.; Tran-Dubé, M.; Waldron, G. J.; Wang, F.; Warmus, J. S. Discovery of potent, selective, and peripherally restricted pan-Trk kinase inhibitors for the treatment of pain. J. Med. Chem. 2018, 61, 6779– 6800, DOI: 10.1021/acs.jmedchem.8b00633[ACS Full Text], [CAS], Google Scholar209https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXht1SnurfN&md5=65b55ef6cdd82c44680c6c49310df7b2Discovery of Potent, Selective, and Peripherally Restricted Pan-Trk Kinase Inhibitors for the Treatment of PainBagal, Sharan K.; Andrews, Mark; Bechle, Bruce M.; Bian, Jianwei; Bilsland, James; Blakemore, David C.; Braganza, John F.; Bungay, Peter J.; Corbett, Matthew S.; Cronin, Ciaran N.; Cui, Jingrong Jean; Dias, Rebecca; Flanagan, Neil J.; Greasley, Samantha E.; Grimley, Rachel; James, Kim; Johnson, Eric; Kitching, Linda; Kraus, Michelle L.; McAlpine, Indrawan; Nagata, Asako; Ninkovic, Sacha; Omoto, Kiyoyuki; Scales, Stephanie; Skerratt, Sarah E.; Sun, Jianmin; Tran-Dube, Michelle; Waldron, Gareth J.; Wang, Fen; Warmus, Joseph S.Journal of Medicinal Chemistry (2018), 61 (15), 6779-6800CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Hormones of the neurotrophin family: nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) and neurotrophin 4 (NT4) are known to activate the family of Tropomyosin receptor kinases (TrkA, TrkB, TrkC). Moreover, inhibition of the TrkA kinase pathway in pain has been clin. validated by the NGF antibody tanezumab leading to significant interest in the development of small mol. inhibitors of TrkA. Furthermore, Trk inhibitors having an acceptable safety profile will require minimal brain availability. Herein we discuss the discovery of two potent, selective, peripherally restricted, efficacious and well-tolerated series of pan-Trk inhibitors which successfully delivered three candidate quality compds. I, II and III. All three compds. are predicted to possess low metabolic clearance in human that does not proceed via aldehyde oxidase-catalyzed reactions, thus addressing the potential clearance prediction liability assocd. with our current pan-Trk development candidate PF-06273340.
- 210Stachel, S. J.; Sanders, J. M.; Henze, D. A.; Rudd, M. T.; Su, H.-P.; Li, Y.; Nanda, K. K.; Egbertson, M. S.; Manley, P. J.; Jones, K. L. G.; Brnardic, E. J.; Green, A.; Grobler, J. A.; Hanney, B.; Leitl, M.; Lai, M.-T.; Munshi, V.; Murphy, D.; Rickert, K.; Riley, D.; Krasowska-Zoladek, A.; Daley, C.; Zuck, P.; Kane, S. A.; Bilodeau, M. T. Maximizing diversity from a kinase screen: identification of novel and selective pan-Trk inhibitors for chronic pain. J. Med. Chem. 2014, 57, 5800– 5816, DOI: 10.1021/jm5006429[ACS Full Text], [CAS], Google Scholar210https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXps1SrsLs%253D&md5=f8aaef0b21eb49eed8004fc18f04dff5Maximizing Diversity from a Kinase Screen: Identification of Novel and Selective pan-Trk Inhibitors for Chronic PainStachel, Shawn J.; Sanders, John M.; Henze, Darrell A.; Rudd, Mike T.; Su, Hua-Poo; Li, Yiwei; Nanda, Kausik K.; Egbertson, Melissa S.; Manley, Peter J.; Jones, Kristen L. G.; Brnardic, Edward J.; Green, Ahren; Grobler, Jay A.; Hanney, Barbara; Leitl, Michael; Lai, Ming-Tain; Munshi, Vandna; Murphy, Dennis; Rickert, Keith; Riley, Daniel; Krasowska-Zoladek, Alicja; Daley, Christopher; Zuck, Paul; Kane, Stephanie A.; Bilodeau, Mark T.Journal of Medicinal Chemistry (2014), 57 (13), 5800-5816CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)We have identified several series of small mol. inhibitors of TrkA with unique binding modes. The starting leads were chosen to maximize the structural and binding mode diversity derived from a high throughput screen of our internal compd. collection. These leads were optimized for potency and selectivity employing a structure based drug design approach adhering to the principles of ligand efficiency to maximize binding affinity without overly relying on lipophilic interactions. This endeavor resulted in the identification of several small mol. pan-Trk inhibitor series that exhibit high selectivity for TrkA/B/C vs. a diverse panel of kinases. We have also demonstrated efficacy in both inflammatory and neuropathic pain models upon oral dosing. Herein we describe the identification process, hit-to-lead progression, and binding profiles of these selective pan-Trk kinase inhibitors.
- 211Turk, S.; Merget, B.; Eid, S.; Fulle, S. From cancer to pain target by automated selectivity inversion of a clinical candidate. J. Med. Chem. 2018, 61, 4851– 4859, DOI: 10.1021/acs.jmedchem.8b00140[ACS Full Text], [CAS], Google Scholar211https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpt12hurc%253D&md5=8e29a51d656eb52a41d9abc6fc22ca59From Cancer to Pain Target by Automated Selectivity Inversion of a Clinical CandidateTurk, Samo; Merget, Benjamin; Eid, Sameh; Fulle, SimoneJournal of Medicinal Chemistry (2018), 61 (11), 4851-4859CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Elimination of inadvertent binding is crucial for inhibitor design targeting conserved protein classes like kinases. Compds. in clin. trials provide a rich source for initiating drug design efforts by exploiting such secondary binding events. Considering both aspects, we shifted the selectivity of tozasertib, originally developed against AurA as cancer target, toward the pain target TrkA. First, selectivity-detg. features in binding pockets were identified by fusing interaction grids of several key and off-target conformations. A focused library was subsequently created and prioritized using a multiobjective selection scheme that filters for selective and highly active compds. based on orthogonal methods grounded in computational chem. and machine learning. Eighteen high-ranking compds. were synthesized and exptl. tested. The top-ranked compd. has 10000-fold improved selectivity vs. AurA, nanomolar cellular activity, and is highly selective in a kinase panel. This was achieved in a single round of automated in silico optimization, highlighting the power of recent advances in computer-aided drug design to automate design and selection processes.
- 212Bagal, S. K.; Omoto, K.; Blakemore, D. C.; Bungay, P. J.; Bilsland, J. G.; Clarke, P. J.; Corbett, M. S.; Cronin, C. N.; Cui, J. J.; Dias, R.; Flanagan, N. J.; Greasley, S. E.; Grimley, R.; Johnson, E.; Fengas, D.; Kitching, L.; Kraus, M. L.; McAlpine, I.; Nagata, A.; Waldron, G. J.; Warmus, J. S. Discovery of allosteric, potent, subtype selective, and peripherally restricted TrkA kinase inhibitors. J. Med. Chem. 2019, 62, 247– 265, DOI: 10.1021/acs.jmedchem.8b00280[ACS Full Text], [CAS], Google Scholar212https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXotVahtL4%253D&md5=b83acaa8a60a65cc78aeabe1215cc026Discovery of Allosteric, Potent, Subtype Selective, and Peripherally Restricted TrkA Kinase InhibitorsBagal, Sharan K.; Omoto, Kiyoyuki; Blakemore, David C.; Bungay, Peter J.; Bilsland, James G.; Clarke, Philip J.; Corbett, Matthew S.; Cronin, Ciaran N.; Cui, J. Jean; Dias, Rebecca; Flanagan, Neil J.; Greasley, Samantha E.; Grimley, Rachel; Johnson, Eric; Fengas, David; Kitching, Linda; Kraus, Michelle L.; McAlpine, Indrawan; Nagata, Asako; Waldron, Gareth J.; Warmus, Joseph S.Journal of Medicinal Chemistry (2019), 62 (1), 247-265CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Tropomyosin receptor kinases (TrkA, TrkB, TrkC) are activated by hormones of the neurotrophin family: nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4). Moreover, the NGF antibody tanezumab has provided clin. proof of concept for inhibition of the TrkA kinase pathway in pain leading to significant interest in the development of small mol. inhibitors of TrkA. However, achieving TrkA subtype selectivity over TrkB and TrkC via a Type I and Type II inhibitor binding mode has proven challenging and Type III or Type IV allosteric inhibitors may present a more promising selectivity design approach. Furthermore, TrkA inhibitors with minimal brain availability are required to deliver an appropriate safety profile. Herein, we describe the discovery of a highly potent, subtype selective, peripherally restricted, efficacious, and well-tolerated series of allosteric TrkA inhibitors that culminated in the delivery of candidate quality compd. 23.
- 213Nwosu, L. N.; Mapp, P. I.; Chapman, V.; Walsh, D. A. Blocking the tropomyosin receptor kinase A (TrkA) receptor inhibits pain behaviour in two rat models of osteoarthritis. Ann. Rheum. Dis. 2016, 75, 1246– 1254, DOI: 10.1136/annrheumdis-2014-207203[Crossref], [PubMed], [CAS], Google Scholar213https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXivV2qtrc%253D&md5=a0159f007c97c40704266844aad93ca1Blocking the tropomyosin receptor kinase A (TrkA) receptor inhibits pain behaviour in two rat models of osteoarthritisNwosu, Lilian N.; Mapp, Paul I.; Chapman, Victoria; Walsh, David A.Annals of the Rheumatic Diseases (2016), 75 (6), 1246-1254CODEN: ARDIAO; ISSN:0003-4967. (BMJ Publishing Group)Objectives: Tropomyosin receptor kinase A (TrkA) mediates nociceptor sensitization by nerve growth factor (NGF), but it is unknown whether selective TrkA inhibition will be an effective strategy for treating osteoarthritis (OA) pain. We detd. the effects of a TrkA inhibitor (AR786) on pain behavior, synovitis and joint pathol. in two rat OA models. Methods: Knee OA was induced in rats by intraarticular monosodium-iodoacetate (MIA) injection or meniscal transection (MNX) and compared with saline injected or sham-operated controls. Pain behavior was assessed as wt.-bearing asymmetry and paw withdrawal threshold to punctate stimulation. Oral doses (30 mg/kg) of AR786 or vehicle were administered twice daily in either preventive (day -1 to -27) or treatment (day 14-28) protocols. Effect maintenance was evaluated for 2 wk after treatment discontinuation. Alterations in knee structure (cartilage, subchondral bone and synovium) were examd. by macroscopic visualization of articular surfaces and histopathol. Results: Preventive AR786 treatment inhibited pain behavior development and therapeutic treatment attenuated established pain behavior. Wt.-bearing asymmetry increased 1 wk after treatment discontinuation, but remained less than in vehicle-treated arthritic rats, whereas paw withdrawal thresholds returned to levels of untreated rats within 5 days of treatment discontinuation. AR786 treatment reduced MIA-induced synovitis and did not significantly affect osteochondral pathol. in either model. Conclusions: Blocking NGF activity by inhibiting TrkA reduced pain behavior in two rat models of OA. Analgesia was obsd. both using preventive and treatment protocols, and was sustained after treatment discontinuation. Selective inhibitors of TrkA therefore hold potential for OA pain relief.
- 214Liu, X.; Chan, C.-B.; Qi, Q.; Xiao, G.; Luo, H. R.; He, X.; Ye, K. Optimization of a small Tropomyosin-related kinase B (TrkB) agonist 7,8-dihydroxyflavone active in mouse models of depression. J. Med. Chem. 2012, 55, 8524– 8537, DOI: 10.1021/jm301099x[ACS Full Text], [CAS], Google Scholar214https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlGkurjM&md5=0d018a4f03a45e67728bda926371f844Optimization of a Small Tropomyosin-Related Kinase B (TrkB) Agonist 7,8-Dihydroxyflavone Active in Mouse Models of DepressionLiu, Xia; Chan, Chi-Bun; Qi, Qi; Xiao, Ge; Luo, Hongbo R.; He, Xiaolin; Ye, KeqiangJournal of Medicinal Chemistry (2012), 55 (19), 8524-8537CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Structure-activity relationship study shows that the catechol group in 7,8-dihdyroxyflavone, a selective small TrkB receptor agonist, is crit. for agonistic activity. To improve the poor pharmacokinetic profiles intrinsic to catechol-contg. mols. and to elevate the agonistic effect of the lead compd., we initiated the lead optimization campaign by synthesizing various bioisosteric derivs. Here we show that the optimized 2-methyl-8-(4'-(pyrrolidin-1-yl)phenyl)chromeno[7,8-d]imidazol-6(1H)-one deriv. possesses enhanced TrkB stimulatory activity. Chronic oral administration of this compd. significantly reduces the immobility in forced swim test and tail suspension test, two classical antidepressant behavioral animal models, which is accompanied by robust TrkB activation in hippocampus of mouse brain. Further, in vitro ADMET studies demonstrate that this compd. possesses the improved features compared to the previous lead compd. Hence, this optimized compd. may act as a promising lead candidate for in-depth drug development for treating various neurol. disorders including depression.
- 215Korkmaz, O. T.; Aytan, N.; Carreras, I.; Choi, J. K.; Kowall, N. W.; Jenkins, B. G.; Dedeoglu, A. 7,8-Dihydroxyflavone improves motor performance and enhances lower motor neuronal survival in a mouse model of amyotrophic lateral sclerosis. Neurosci. Lett. 2014, 566, 286– 291, DOI: 10.1016/j.neulet.2014.02.058[Crossref], [PubMed], [CAS], Google Scholar215https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXmt1agu7g%253D&md5=23684b399bba0362747877939e755dcc7,8-Dihydroxyflavone improves motor performance and enhances lower motor neuronal survival in a mouse model of amyotrophic lateral sclerosisKorkmaz, Orhan Tansel; Aytan, Nurgul; Carreras, Isabel; Choi, Ji-Kyung; Kowall, Neil W.; Jenkins, Bruce G.; Dedeoglu, AlpaslanNeuroscience Letters (2014), 566 (), 286-291CODEN: NELED5; ISSN:0304-3940. (Elsevier Ireland Ltd.)Amyotrophic lateral sclerosis (ALS) is an enigmatic neurodegenerative disorder without any effective treatment characterized by loss of motor neurons (MNs) that results in rapidly progressive motor weakness and early death due to respiratory failure. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family known to play a prominent role in the differentiation and survival of MNs. The flavonoid 7,8-dihydroxyflavone (7,8-DHF) is a potent and selective small mol. tyrosine kinase receptor B (TrkB) agonist that mimics the effects of BDNF. In the present study, we evaluated the neuroprotective effects of 7,8-DHF in a transgenic ALS mouse model (SOD1G93A). We found that chronic administration of 7,8-DHF significantly improved motor deficits, and preserved spinal MNs count and dendritic spines in SOD1G93A mice. These data suggest that 7,8-DHF should be considered as a potential therapy for ALS and the other motor neuron diseases.
- 216Koch, P.; Gehringer, M.; Laufer, S. A. Inhibitors of c-Jun N-terminal kinases: an update. J. Med. Chem. 2015, 58, 72– 95, DOI: 10.1021/jm501212r[ACS Full Text], [CAS], Google Scholar216https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvFOhsb%252FN&md5=0d1c32e1463de951c8b47f35882f90abInhibitors of c-Jun N-Terminal Kinases: An UpdateKoch, Pierre; Gehringer, Matthias; Laufer, Stefan A.Journal of Medicinal Chemistry (2015), 58 (1), 72-95CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The c-Jun N-terminal kinases (JNKs) are serine/threonine kinases implicated in the pathogenesis of various diseases. Recent advances in the development of novel inhibitors of JNKs will be reviewed. Significant progress in the design of JNK inhibitors displaying selectivity vs. other kinases has been achieved within the past 4 years. However, the development of isoform selective JNK inhibitors is still an open task.
- 217Swantek, J. L.; Cobb, M. H.; Geppert, T. D. Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) is required for lipopolysaccharide stimulation of tumor necrosis factor α (TNF-α) translation: glucocorticoids inhibit TNF-α translation by blocking JNK/SAPK. Mol. Cell. Biol. 1997, 17, 6274– 6282, DOI: 10.1128/MCB.17.11.6274[Crossref], [PubMed], [CAS], Google Scholar217https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXntVSjsb4%253D&md5=2c62495710ab59a5c07905770ebbf437Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) is required for lipopolysaccharide stimulation of tumor necrosis factor α (TNF-α) translation: glucocorticoids inhibit TNF-α translation by blocking JNK/SAPKSwantek, Jennifer L.; Cobb, Melanie H.; Geppert, Thomas D.Molecular and Cellular Biology (1997), 17 (11), 6274-6282CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)The adverse effects of lipopolysaccharide (LPS) are mediated primarily by TNF-α. TNF-α prodn. by LPS-stimulated macrophages is regulated at the levels of both transcription and translation. It has previously been shown that several mitogen-activated protein kinases (MAPKs) are activated in response to LPS. The authors set out to det. which MAPK signaling pathways are activated in this system and which MAPK pathways are required for TNF-α gene transcription or TNF-α mRNA translation. The authors confirm activation of the MAPK family members extracellular-signal-regulated kinases 1 and 2 (ERK1 and ERK2), p38, and Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), as well as activation of the immediate upstream MAPK activators MAPK/ERK kinases 1 and 4 (MEK1 and MEK4). They also demonstrate that LPS also activates MEK2, MEK3, and MEK6. Furthermore, the authors demonstrate that dexamethasone, which inhibits the prodn. of cytokines, including TNF-α, inhibits LPS induction of JNK/SAPK activity but not that of p38, ERK1 and ERK2, or MEK3, MEK4, or MEK6. Dexamethasone also blocks the sorbitol but not anisomycin stimulation of JNK/SAPK activity. A kinase-defective mutant of SAPKβ, SAPKβ K-A, blocked translation of TNF-α, as detd. by using a TNF-α translational reporting system. Finally, overexpression of wild-type SAPKβ was able to overcome the dexamethasone-induced block of TNF-α translation. Thus, 3 MAPK family members and their upstream activators are stimulated by LPS and JNK/SAPK is required for LPS-induced translation of TNF-α mRNA. A novel mechanism by which dexamethasone inhibits translation of TNF-α is also revealed.
- 218Gaillard, P.; Jeanclaude-Etter, I.; Ardissone, V.; Arkinstall, S.; Cambet, Y.; Camps, M.; Chabert, C.; Church, D.; Cirillo, R.; Gretener, D.; Halazy, S.; Nichols, A.; Szyndralewiez, C.; Vitte, P. A.; Gotteland, J. P. Design and synthesis of the first-generation of novel potent, selective, and in vivo active (benzothiazol-2-yl)acetonitrile inhibitors of the c-Jun N-terminal kinase. J. Med. Chem. 2005, 48, 4596– 4607, DOI: 10.1021/jm0310986[ACS Full Text], [CAS], Google Scholar218https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXkvVGks70%253D&md5=3355648f8e198bfeebb9e505d47f9d77Design and Synthesis of the First Generation of Novel Potent, Selective, and in Vivo Active (Benzothiazol-2-yl)acetonitrile Inhibitors of the c-Jun N-Terminal KinaseGaillard, Pascale; Jeanclaude-Etter, Isabelle; Ardissone, Vittoria; Arkinstall, Steve; Cambet, Yves; Camps, Montserrat; Chabert, Christian; Church, Dennis; Cirillo, Rocco; Gretener, Denise; Halazy, Serge; Nichols, Anthony; Szyndralewiez, Cedric; Vitte, Pierre-Alain; Gotteland, Jean-PierreJournal of Medicinal Chemistry (2005), 48 (14), 4596-4607CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Several lines of evidence support the hypothesis that c-Jun N-terminal kinase (JNKs) plays a crit. role in a wide range of diseases including cell death (apoptosis)-related disorders (neurodegenerative diseases, brain, heart, and renal ischemia, epilepsy) and inflammatory disorders (multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases). Screening of an internal compd. collection for inhibitors of JNK3 led to the identification of (benzothiazol-2-yl)acetonitrile derivs. as potent and selective JNK1, -2, -3 inhibitors. Starting from initial hit I [R = Cl, R1 = Br] (AS007149), the chem. and initial structure-activity relationship (SAR) of this novel and unique kinase inhibitor template were explored. Investigation of the SAR rapidly revealed that the benzothiazol-2-ylacetonitrile pyrimidine core was crucial to retain a good level of potency on rat JNK3. Therefore, I [R = Cl, R1 = H] was further optimized by exploring a no. of distal combinations in place of the chlorine atom. This led to the observation that the presence of an arom. group, two carbons away from the aminopyrimidine moiety and bearing substituents conferring hydrogen bond acceptor (HBA) properties, could improve the potency. Further improvements to the biol. and biopharmaceutical profile of the most promising compds. were performed, resulting in the discovery of I [R = 2-(3-pyridinyl)ethyl, R1 = H] (AS601245). The in vitro and in vivo anti-inflammatory potential of this new JNK inhibitor was investigated and found to demonstrate efficacy per oral route in an exptl. model of rheumatoid arthritis (RA).
- 219Colombo, A.; Bastone, A.; Ploia, C.; Sclip, A.; Salmona, M.; Forloni, G.; Borsello, T. JNK regulates APP cleavage and degradation in a model of Alzheimer’s disease. Neurobiol. Dis. 2009, 33, 518– 525, DOI: 10.1016/j.nbd.2008.12.014[Crossref], [PubMed], [CAS], Google Scholar219https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXitVSjt74%253D&md5=7e7ba36777e13a3bf5430b8be9c1cc14JNK regulates APP cleavage and degradation in a model of Alzheimer's diseaseColombo, Alessio; Bastone, Antonio; Ploia, Cristina; Sclip, Alessandra; Salmona, Mario; Forloni, Gianluigi; Borsello, TizianaNeurobiology of Disease (2009), 33 (3), 518-525CODEN: NUDIEM; ISSN:0969-9961. (Elsevier B.V.)Secretion of Amyloid-beta peptide (Aβ) circulating oligomers and their aggregate forms derived by processing of beta-amyloid precursor protein (APP) are a key event in Alzheimer's disease (AD). We show that phosphorylation of APP on threonine 668 may play a role in APP metab. in H4-APPsw cell line, a degenerative AD model. We proved that JNK plays a fundamental role in this phosphorylation since its specific inhibition, with the JNK inhibitor peptide (D-JNKI1), induced APP degrdn. and prevented APP phosphorylation at T668. This results in a significant drop of βAPPs, Aβ fragments and Aβ circulating oligomers. Moreover the D-JNKI1 treatment produced a switch in the APP metab., since the peptide reduced the rate of the amyloidogenic processing in favor of the non-amyloidogenic one. All together our results suggest an important link between APP metab. and the JNK pathway and contribute to shed light on the mol. signalling pathway of this disease indicating JNK as an innovative target for AD therapy.
- 220Ploia, C.; Antoniou, X.; Sclip, A.; Grande, V.; Cardinetti, D.; Colombo, A.; Canu, N.; Benussi, L.; Ghidoni, R.; Forloni, G.; Borsello, T. JNK plays a key role in tau hyperphosphorylation in Alzheimer’s disease models. J. Alzheimer's Dis. 2011, 26, 315– 329, DOI: 10.3233/JAD-2011-110320[Crossref], [PubMed], [CAS], Google Scholar220https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFeks7fF&md5=2f80e53c135240675ffacf5041278e06JNK Plays a Key Role in Tau Hyperphosphorylation in Alzheimer's Disease ModelsPloia, Cristina; Antoniou, Xanthi; Sclip, Alessandra; Grande, Valentina; Cardinetti, Daniele; Colombo, Alessio; Canu, Nadia; Benussi, Luisa; Ghidoni, Roberta; Forloni, Gianluigi; Borsello, TizianaJournal of Alzheimer's Disease (2011), 26 (2), 315-329CODEN: JADIF9; ISSN:1387-2877. (IOS Press)Alzheimer's disease (AD) is a major clin. concern, and the search for new mols. to combat disease progression remains important. One of the major hallmarks in AD pathogenesis is the hyperphosphorylation of tau and subsequent formation of neurofibrillary tangles. Several kinases are involved in this process. Amongst them, c-Jun N-terminal kinases (JNKs) are activated in AD brains and are also assocd. with the development of amyloid plaques. This study was designed to investigate the contribution of JNK in tau hyperphosphorylation and whether it may represent a potential therapeutic target for the fight against AD. The specific inhibition of JNK by the cell permeable peptide D-JNKI-1 led to a redn. of p-tau at S202/T205 and S422, two established target sites of JNK, in rat neuronal cultures and in human fibroblasts cultures. Similarly, D-JNKI-1 reduced p-tau at S202/T205 in an in vivo model of AD (TgCRND8 mice). Our findings support the fundamental role of JNK in the regulation of tau hyperphosphorylation and subsequently in AD pathogenesis.
- 221Zhou, Q.; Wang, M.; Du, Y.; Zhang, W.; Bai, M.; Zhang, Z.; Li, Z.; Miao, J. Inhibition of c-Jun N-terminal kinase activation reverses Alzheimer disease phenotypes in APPswe/PS1dE9 mice. Ann. Neurol. 2015, 77, 637– 654, DOI: 10.1002/ana.24361[Crossref], [PubMed], [CAS], Google Scholar221https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXlt1WqtLc%253D&md5=0f6ce5cdf905ffc7aea5cb38d90de401Inhibition of c-Jun N-terminal kinase activation reverses Alzheimer disease phenotypes in APPswe/PS1dE9 miceZhou, Qiong; Wang, Man; Du, Ying; Zhang, Wei; Bai, Miao; Zhang, Zhuo; Li, Zhuyi; Miao, JiantingAnnals of Neurology (2015), 77 (4), 637-654CODEN: ANNED3; ISSN:0364-5134. (John Wiley & Sons, Inc.)Objective : Growing evidence indicates that the activation of c-Jun N-terminal kinase (JNK) is implicated in the multiple major pathol. features of Alzheimer disease (AD). However, whether specific inhibition of JNK activation could prevent disease progression in adult transgenic AD models at moderate stage remains unknown. Here we first investigated the potential disease-modifying therapeutic effect of systemic administration of SP600125, a small-mol. JNK-specific inhibitor, in middle-aged APPswe/PS1dE9 mice. Methods : Using behavioral, histol., and biochem. methods, outcomes of SP600125 treatment on neuropathol. and cognitive deficits were studied in APPswe/PS1dE9 mice. Results : Compared with vehicle-treated APPswe/PS1dE9 mice, chronic treatment of SP600125 for 12 wk potently inhibited JNK activation, which resulted in a marked improvement of behavioral measures of cognitive deficits and a dramatic redn. in amyloid plaque burden, β-amyloid prodn., tau hyperphosphorylation, inflammatory responses, and synaptic loss in these transgenic animals. In particular, we found that SP600125 treatment strongly promoted nonamyloidogenic amyloid precursor protein (APP) processing and inhibited amyloidogenic APP processing via regulating APP-cleavage secretase expression (ie, ADAM10, BACE1, and PS1) in APPswe/PS1dE9 mice. Interpretation : Our findings demonstrate that chronic SP600125 treatment is powerfully effective in slowing down disease progression by markedly reducing multiple pathol. features and ameliorating cognitive deficits assocd. with AD. This study highlights the concept that active JNK actually contributes to the development of the disease, and provides crit. preclin. evidence that specific inhibition of JNK activation by SP600125 treatment may be a novel promising disease-modifying therapeutic strategy for the treatment of AD.
- 222Eynott, P. R.; Nath, P.; Leung, S. Y.; Adcock, I. M.; Bennett, B. L.; Chung, K. F. Allergen-induced inflammation and airway epithelial and smooth muscle cell proliferation: role of Jun N-terminal kinase. Br. J. Pharmacol. 2003, 140, 1373– 1380, DOI: 10.1038/sj.bjp.0705569[Crossref], [PubMed], [CAS], Google Scholar222https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhsV2rtQ%253D%253D&md5=ac856cb6e94636a9565a1e8832e3f5baAllergen-induced inflammation and airway epithelial and smooth muscle cell proliferation: Role of Jun N-terminal kinaseEynott, Paul R.; Nath, Puneeta; Leung, Sum-Yee; Adcock, Ian M.; Bennett, Brydon L.; Chung, K. FanBritish Journal of Pharmacology (2003), 140 (8), 1373-1380CODEN: BJPCBM; ISSN:0007-1188. (Nature Publishing Group)1 Chronic cellular inflammation and airway wall remodelling with subepithelial fibrosis and airway smooth muscle (ASM) cell hyperplasia are features of chronic asthma. Jun N-terminal kinase (JNK) may be implicated in these processes by regulating the transcriptional activity of activator protein (AP)-1. 2 The authors examd. the effects of an inhibitor of JNK, SP600125 (anthra [1,9-cd] pyrazole-6 (2 H)-one), in a model of chronic allergic inflammation in the rat. 3 Rats sensitized to ovalbumin (OA) were exposed to OA-aerosol every third day on six occasions and were treated with SP600125 (30 mg kg-1 b.i.d; 360 mg in total) for 12 days, starting after the second through to the sixth OA exposure. The authors measured eosinophilic and T-cell inflammation in the airways, proliferation of ASM cells and epithelial cells by incorporation of bromodeoxyuridine (BrdU), and bronchial responsiveness to acetylcholine. 4 SP600125 significantly reduced the no. of eosinophils and lymphocytes in bronchoalveolar lavage fluid, suppressed eosinophilic and CD2+ T-cell infiltration within the bronchial submucosa, and the increased DNA incorporation in ASM and epithelial cell incorporation. 5 SP600125 did not alter bronchial hyper-responsiveness obsd. after chronic allergen exposure. 6 Pathways regulated by JNK pos. regulate ASM cell proliferation and allergic cellular inflammation following chronic allergen exposure.
- 223Palmer, S. S.; Altan, M.; Denis, D.; Tos, E. G.; Gotteland, J. P.; Osteen, K. G.; Bruner-Tran, K. L.; Nataraja, S. G. Bentamapimod (JNK inhibitor AS602801) induces regression of endometriotic lesions in animal models. Reprod. Sci. 2016, 23, 11– 23, DOI: 10.1177/1933719115600553[Crossref], [PubMed], [CAS], Google Scholar223https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XpvVensrY%253D&md5=f8604d4855f38f0a3888a59cf27f463eBentamapimod (JNK inhibitor AS602801) induces regression of endometriotic lesions in animal modelsPalmer, Stephen S.; Altan, Melis; Denis, Deborah; Tos, Enrico Gillio; Gotteland, Jean-Pierre; Osteen, Kevin G.; Bruner-Tran, Kaylon L.; Nataraja, Selvaraj G.Reproductive Sciences (2016), 23 (1), 11-23CODEN: RSECC3; ISSN:1933-7191. (Sage Publications)Endometriosis is an estrogen (ER)-dependent gynecol. disease caused by the growth of endometrial tissue at extrauterine sites. Current endocrine therapies address the estrogenic aspect of disease and offer some relief from pain but are assocd. with significant side effects. Immune dysfunction is also widely believed to be an underlying contributor to the pathogenesis of this disease. This study evaluated an inhibitor of c-Jun N-terminal kinase, bentamapimod (AS602801), which interrupts immune pathways, in 2 rodent endometriosis models. Treatment of nude mice bearing xenografts biopsied from women with endometriosis (BWE) with 30 mg/kg AS602801 caused 29% regression of lesion. Medroxyprogesterone acetate (MPA) or progesterone (PR) alone did not cause regression of BWE lesions, but combining 10 mg/kg AS602801 with MPA caused 38% lesion regression. In human endometrial organ cultures (from healthy women), treatment with AS602801 or MPA reduced matrix metalloproteinase-3 (MMP-3) release into culture medium. In organ cultures established with BWE, PR or MPA failed to inhibit MMP-3 secretion, whereas AS602801 alone or MPA + AS602801 suppressed MMP-3 prodn. In an autologous rat endometriosis model, AS602801 caused 48% regression of lesions compared to GnRH antagonist Antide (84%). AS602801 reduced inflammatory cytokines in endometriotic lesions, while levels of cytokines in ipsilateral horns were unaffected. Furthermore, AS602801 enhanced natural killer cell activity, without apparent neg. effects on uterus. These results indicate that bentamapimod induced regression of endometriotic lesions in endometriosis rodent animal models without suppressing ER action. c-Jun N-terminal kinase inhibition mediated a comprehensive redn. in cytokine secretion and moreover was able to overcome PR resistance.
- 224Plantevin Krenitsky, V.; Nadolny, L.; Delgado, M.; Ayala, L.; Clareen, S. S.; Hilgraf, R.; Albers, R.; Hegde, S.; D’Sidocky, N.; Sapienza, J.; Wright, J.; McCarrick, M.; Bahmanyar, S.; Chamberlain, P.; Delker, S. L.; Muir, J.; Giegel, D.; Xu, L.; Celeridad, M.; Lachowitzer, J.; Bennett, B.; Moghaddam, M.; Khatsenko, O.; Katz, J.; Fan, R.; Bai, A.; Tang, Y.; Shirley, M. A.; Benish, B.; Bodine, T.; Blease, K.; Raymon, H.; Cathers, B. E.; Satoh, Y. Discovery of CC-930, an orally active anti-fibrotic JNK inhibitor. Bioorg. Med. Chem. Lett. 2012, 22, 1433– 1438, DOI: 10.1016/j.bmcl.2011.12.027[Crossref], [PubMed], [CAS], Google Scholar224https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhslCls7c%253D&md5=fc99284fc784d1649286c95888a94e5eDiscovery of CC-930, an orally active anti-fibrotic JNK inhibitorPlantevin Krenitsky, Veronique; Nadolny, Lisa; Delgado, Mercedes; Ayala, Leticia; Clareen, Steven S.; Hilgraf, Robert; Albers, Ronald; Hegde, Sayee; D'Sidocky, Neil; Sapienza, John; Wright, Jonathan; McCarrick, Meg; Bahmanyar, Sogole; Chamberlain, Philip; Delker, Silvia L.; Muir, Jeff; Giegel, David; Xu, Li; Celeridad, Maria; Lachowitzer, Jeff; Bennett, Brydon; Moghaddam, Mehran; Khatsenko, Oleg; Katz, Jason; Fan, Rachel; Bai, April; Tang, Yang; Shirley, Michael A.; Benish, Brent; Bodine, Tracey; Blease, Kate; Raymon, Heather; Cathers, Brian E.; Satoh, YoshitakaBioorganic & Medicinal Chemistry Letters (2012), 22 (3), 1433-1438CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)In this Letter we describe the discovery of potent, selective, and orally active aminopurine JNK inhibitors. Improving the physico-chem. properties as well as increasing the potency and selectivity of a subseries with rat plasma exposure, led to the identification of four structurally diverse inhibitors. Differentiation based on PK profiles in multiple species as well as activity in a chronic efficacy model led to the identification of 1 (CC-930, I) as a development candidate, which is currently in Phase II clin. trial for IPF.
- 225Kaoud, T. S.; Mitra, S.; Lee, S.; Taliaferro, J.; Cantrell, M.; Linse, K. D.; Van Den Berg, C. L.; Dalby, K. N. Development of JNK2-selective peptide inhibitors that inhibit breast cancer cell migration. ACS Chem. Biol. 2011, 6, 658– 666, DOI: 10.1021/cb200017n[ACS Full Text], [CAS], Google Scholar225https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXkt1Wnu7k%253D&md5=7cf41c3797ada88ab0bdde9a087cfec9Development of JNK2-Selective Peptide Inhibitors That Inhibit Breast Cancer Cell MigrationKaoud, Tamer S.; Mitra, Shreya; Lee, Sunbae; Taliaferro, Juliana; Cantrell, Michael; Linse, Klaus D.; Van Den Berg, Carla L.; Dalby, Kevin N.ACS Chemical Biology (2011), 6 (6), 658-666CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)Despite their lack of selectivity toward c-Jun N-terminal kinase (JNK) isoforms, peptides derived from the JIP (JNK Interacting Protein) scaffolds linked to the cell-penetrating peptide TAT are widely used to investigate JNK-mediated signaling events. To engineer an isoform-selective peptide inhibitor, several JIP-based peptide sequences were designed and tested. A JIP sequence connected through a flexible linker to either the N-terminus of an inverted TAT sequence (JIP10-Δ-TATi) or to a poly arginine sequence (JIP10-Δ-R9) enabled the potent inhibition of JNK2 (IC50 ≈ 90 nM) and exhibited 10-fold selectivity for JNK2 over JNK1 and JNK3. Examn. of both peptides in HEK293 cells revealed a potent ability to inhibit the induction of both JNK activation and c-Jun phosphorylation in cells treated with anisomycin. Notably, Western blot anal. indicates that only a fraction of total JNK must be activated to elicit robust c-Jun phosphorylation. To examine the potential of each peptide to selectively modulate JNK2 signaling in vivo, their ability to inhibit the migration of Polyoma Middle-T Antigen Mammary Tumor (PyVMT) cells was assessed. PyVMTjnk2-/- cells exhibit a lower migration potential compared to PyVMTjnk2+/+ cells, and this migration potential is restored through the overexpression of GFP-JNK2α. Both JIP10-Δ-TATi and JIP10-Δ-R9 inhibit the migration of PyVMTjnk2+/+ cells and PyVMTjnk2-/- cells expressing GFP-JNK2α. However, neither peptide inhibits the migration of PyVMTjnk2-/- cells. A control form of JIP10-Δ-TATi contg. a single leucine to arginine mutation lacks ability to inhibit JNK2 in vitro cell-free and cell-based assays and does not inhibit the migration of PyVMTjnk2+/+ cells. Together, these data suggest that JIP10-Δ-TATi and JIP10-Δ-R9 inhibit the migration of PyVMT cells through the selective inhibition of JNK2. Finally, the mechanism of inhibition of a D-retro-inverso JIP peptide, previously reported to inhibit JNK, was examd. and found to inhibit p38MAPKα in an in vitro cell-free assay with little propensity to inhibit JNK isoforms.
- 226Dou, X.; Huang, H.; Li, Y.; Jiang, L.; Wang, Y.; Jin, H.; Jiao, N.; Zhang, L.; Zhang, L.; Liu, Z. Multistage screening reveals 3-substituted indolin-2-one derivatives as novel and isoform-selective c-jun N-terminal kinase 3 (JNK3) inhibitors: implications to drug discovery for potential treatment of neurodegenerative diseases. J. Med. Chem. 2019, 62, 6645– 6664, DOI: 10.1021/acs.jmedchem.9b00537[ACS Full Text], [CAS], Google Scholar226https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtlamsbbM&md5=ed74af99cc8e89a98874fcf6e9bcdd4eMultistage Screening Reveals 3-Substituted Indolin-2-one Derivatives as Novel and Isoform-Selective c-Jun N-terminal Kinase 3 (JNK3) Inhibitors: Implications to Drug Discovery for Potential Treatment of Neurodegenerative DiseasesDou, Xiaodong; Huang, Huixia; Li, Yibo; Jiang, Lan; Wang, Yanxing; Jin, Hongwei; Jiao, Ning; Zhang, Lihe; Zhang, Liangren; Liu, ZhenmingJournal of Medicinal Chemistry (2019), 62 (14), 6645-6664CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Alzheimer's disease (AD) is one of the most challenging diseases around the world with no effective clin. treatment. Previous studies have suggested c-Jun N-terminal kinase 3 (JNK3) as an attractive therapeutic target for AD. Herein, we report 3-substituted indolin-2-one derivs. as the first isoform-selective JNK3 inhibitors by multistage screening. In this study, comparative structure-based virtual screening was performed, and J30-8 was identified with a half-maximal inhibitory concn. of 40 nM, which exhibited over 2500-fold isoform selectivity and marked kinome-wide selectivity. Further study indicated that 1 μM J30-8 exhibited neuroprotective activity in vitro so as to alleviate the spatial memory impairment in vivo through reducing plaque burden and inhibiting the phosphorylation of JNKs, Aβ precursor protein, and Tau protein. All of these indicated J30-8 as proved isoform-selective JNK3 inhibitors that might serve as a useful tool for further JNK3 studies with AD as well as for the development of JNK3 inhibitors for the potential treatment of neurodegenerative diseases.
- 227Zheng, K.; Iqbal, S.; Hernandez, P.; Park, H.; LoGrasso, P. V.; Feng, Y. Design and synthesis of highly potent and isoform selective JNK3 inhibitors: SAR studies on aminopyrazole derivatives. J. Med. Chem. 2014, 57, 10013– 10030, DOI: 10.1021/jm501256y[ACS Full Text], [CAS], Google Scholar227https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvFWns7fJ&md5=fd826c83f112d7270ef669b74e6ef6f0Design and Synthesis of Highly Potent and Isoform Selective JNK3 Inhibitors: SAR Studies on Aminopyrazole DerivativesZheng, Ke; Iqbal, Sarah; Hernandez, Pamela; Park, HaJeung; LoGrasso, Philip V.; Feng, YangboJournal of Medicinal Chemistry (2014), 57 (23), 10013-10030CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The c-jun N-terminal kinase 3 (JNK3) is expressed primarily in the brain. Numerous reports have shown that inhibition of JNK3 is a promising strategy for treatment of neurodegeneration. The optimization of aminopyrazole-based JNK3 inhibitors with improved potency, isoform selectivity, and pharmacol. properties by structure-activity relationship (SAR) studies utilizing biochem. and cell-based assays, and structure-based drug design is reported. These inhibitors had high selectivity over JNK1 and p38α, minimal cytotoxicity, potent inhibition of 6-OHDA-induced mitochondrial membrane potential dissipation and ROS generation, and good drug metab. and pharmacokinetic (DMPK) properties for iv dosing. 26n was profiled against 464 kinases and was found to be highly selective hitting only seven kinases with >80% inhibition at 10 μM. Moreover, 26n showed good soly., good brain penetration, and good DMPK properties. Finally, the crystal structure of 26k in complex with JNK3 was solved at 1.8 Å to explore the binding mode of aminopyrazole based JNK3 inhibitors.
- 228Estrada, A. A.; Sweeney, Z. K. Chemical biology of Leucine-rich repeat kinase 2 (LRRK2) inhibitors. J. Med. Chem. 2015, 58, 6733– 6746, DOI: 10.1021/acs.jmedchem.5b00261[ACS Full Text], [CAS], Google Scholar228https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXntFGiu7g%253D&md5=37336d97c3c51dcea44df4f7a51837c5Chemical Biology of Leucine-Rich Repeat Kinase 2 (LRRK2) InhibitorsEstrada, Anthony A.; Sweeney, Zachary K.Journal of Medicinal Chemistry (2015), 58 (17), 6733-6746CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)There is an urgent need for the development of Parkinson's disease (PD) treatments that can slow disease progression. The leucine-rich repeat kinase 2 (LRRK2) protein has been genetically and functionally linked to PD, and modulation of LRRK2 enzymic activity has been proposed as a novel therapeutic strategy. In this review, we describe the bioactivity of selected small mols. that have been used to inhibit LRRK2 kinase activity in vitro or in vivo. These compds. are important tools for understanding the cellular biol. of LRRK2 and for evaluating the potential of LRRK2 inhibitors as disease-modifying PD therapies.
- 229Kang, U. B.; Marto, J. A. Leucine-rich repeat kinase 2 and Parkinson’s disease. Proteomics 2017, 17, 1600092, DOI: 10.1002/pmic.201600092
- 230Domingos, S.; Duarte, T.; Saraiva, L.; Guedes, R. C.; Moreira, R. Targeting leucine-rich repeat kinase 2 (LRRK2) for the treatment of Parkinson’s disease. Future Med. Chem. 2019, 11, 1953– 1977, DOI: 10.4155/fmc-2018-0484[Crossref], [PubMed], [CAS], Google Scholar230https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhslGksbvN&md5=3d91a8d284e5f764daff0e33782dfa05Targeting leucine-rich repeat kinase 2 (LRRK2) for the treatment of Parkinson's diseaseDomingos, Sofia; Duarte, Teresa; Saraiva, Lucilia; Guedes, Rita C.; Moreira, RuiFuture Medicinal Chemistry (2019), 11 (15), 1953-1977CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)A review. Leucine-rich repeat kinase 2 (LRRK2) is a serine-threonine kinase involved in multiple cellular processes and signaling pathways. LRRK2 mutations are assocd. with autosomal-inherited Parkinson's disease (PD), and evidence suggests that LRRK2 pathogenic variants generally increase kinase activity. Therefore, inhibition of LRRK2 kinase function is a promising therapeutic strategy for PD treatment. The search for drug-like mols. capable of reducing LRRK2 kinase activity in PD led to the design of selective LRRK2 inhibitors predicted to be within the CNS drug-like space. This review highlights the journey that translates chem. tools for interrogating the role of LRRK2 in PD into promising drug candidates, addressing the challenges in discovering selective and brain-penetrant LRRK2 modulators and exploring the structure-activity relationship of distinct LRRK2 inhibitors.
- 231Taymans, J. M.; Greggio, E. LRRK2 kinase inhibition as a therapeutic strategy for Parkinson’s disease, where do we stand?. Curr. Neuropharmacol 2016, 14, 214– 225, DOI: 10.2174/1570159X13666151030102847[Crossref], [PubMed], [CAS], Google Scholar231https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XktlCgu74%253D&md5=f68fc6814e2add4836aefe53321d1199LRRK2 Kinase Inhibition as a Therapeutic Strategy for Parkinson's Disease, Where Do We Stand?Taymans, Jean-Marc; Greggio, ElisaCurrent Neuropharmacology (2016), 14 (3), 214-225CODEN: CNUEAN; ISSN:1875-6190. (Bentham Science Publishers Ltd.)One of the most promising therapeutic targets for potential disease modifying treatment of Parkinson's disease (PD) is leucine-rich repeat kinase 2 (LRRK2). Specifically, targeting LRRK2's kinase function has generated a lot of interest from both industry and academia. This work has yielded several published studies showing the feasibility of developing potent, selective and brain permeable LRRK2 kinase inhibitors. The availability of these exptl. drugs is contributing to filling in the gaps in our knowledge on the safety and efficacy of LRRK2 kinase inhibition. Recent studies of LRRK2 kinase inhibition in preclin. models point to potential undesired effects in peripheral tissues such as lung and kidney. Also, while strategies are now emerging to measure target engagement of LRRK2 inhibitors, there remains an important need to expand efficacy studies in preclin. models of progressive PD. Future work in the LRRK2 inhibition field must therefore be directed towards developing mols. and treatment regimens which demonstrate efficacy in mammalian models of disease in conditions where safety liabilities are reduced to a min.
- 232Reith, A. D.; Bamborough, P.; Jandu, K.; Andreotti, D.; Mensah, L.; Dossang, P.; Choi, H. G.; Deng, X.; Zhang, J.; Alessi, D. R.; Gray, N. S. GSK2578215A; a potent and highly selective 2-arylmethyloxy-5-substitutent-N-arylbenzamide LRRK2 kinase inhibitor. Bioorg. Med. Chem. Lett. 2012, 22, 5625– 5629, DOI: 10.1016/j.bmcl.2012.06.104[Crossref], [PubMed], [CAS], Google Scholar232https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtFCgsrfO&md5=b2bf7c7cb191cd297b8f586daca58ab1GSK2578215A; A potent and highly selective 2-arylmethyloxy-5-substitutent-N-arylbenzamide LRRK2 kinase inhibitorReith, Alastair D.; Bamborough, Paul; Jandu, Karamjit; Andreotti, Daniele; Mensah, Lucy; Dossang, Pamela; Choi, Hwan Geun; Deng, Xianming; Zhang, Jinwei; Alessi, Dario R.; Gray, Nathanael S.Bioorganic & Medicinal Chemistry Letters (2012), 22 (17), 5625-5629CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for some forms of Parkinson's disease. Here we report the discovery and characterization of 2-arylmethyloxy-5-subtitutent-N-arylbenzamides with potent LRRK2 activities exemplified by GSK2578215A which exhibits biochem. IC50s of around 10 nM against both wild-type LRRK2 and the G2019S mutant. GSK2578215A exhibits exceptionally high selectivity for LRRK2 across the kinome, substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concn. of 0.3-1.0 μM in cells and in mouse spleen and kidney, but not in brain, following i.p. injection of 100 mg/kg.
- 233Estrada, A. A.; Liu, X.; Baker-Glenn, C.; Beresford, A.; Burdick, D. J.; Chambers, M.; Chan, B. K.; Chen, H.; Ding, X.; DiPasquale, A. G.; Dominguez, S. L.; Dotson, J.; Drummond, J.; Flagella, M.; Flynn, S.; Fuji, R.; Gill, A.; Gunzner-Toste, J.; Harris, S. F.; Heffron, T. P.; Kleinheinz, T.; Lee, D. W.; Le Pichon, C. E.; Lyssikatos, J. P.; Medhurst, A. D.; Moffat, J. G.; Mukund, S.; Nash, K.; Scearce-Levie, K.; Sheng, Z.; Shore, D. G.; Tran, T.; Trivedi, N.; Wang, S.; Zhang, S.; Zhang, X.; Zhao, G.; Zhu, H.; Sweeney, Z. K. Discovery of highly potent, selective, and brain-penetrable leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitors. J. Med. Chem. 2012, 55, 9416– 9433, DOI: 10.1021/jm301020q[ACS Full Text], [CAS], Google Scholar233https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlGktbfO&md5=9fc7ccca9c973a960e7393c79c1255faDiscovery of Highly Potent, Selective, and Brain-Penetrable Leucine-Rich Repeat Kinase 2 (LRRK2) Small Molecule InhibitorsEstrada, Anthony A.; Liu, Xingrong; Baker-Glenn, Charles; Beresford, Alan; Burdick, Daniel J.; Chambers, Mark; Chan, Bryan K.; Chen, Huifen; Ding, Xiao; DiPasquale, Antonio G.; Dominguez, Sara L.; Dotson, Jennafer; Drummond, Jason; Flagella, Michael; Flynn, Sean; Fuji, Reina; Gill, Andrew; Gunzner-Toste, Janet; Harris, Seth F.; Heffron, Timothy P.; Kleinheinz, Tracy; Lee, Donna W.; Le Pichon, Claire E.; Lyssikatos, Joseph P.; Medhurst, Andrew D.; Moffat, John G.; Mukund, Susmith; Nash, Kevin; Scearce-Levie, Kimberly; Sheng, Zejuan; Shore, Daniel G.; Tran, Thuy; Trivedi, Naimisha; Wang, Shumei; Zhang, Shuo; Zhang, Xiaolin; Zhao, Guiling; Zhu, Haitao; Sweeney, Zachary K.Journal of Medicinal Chemistry (2012), 55 (22), 9416-9433CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)There is a high demand for potent, selective, and brain-penetrant small mol. inhibitors of leucine-rich repeat kinase 2 (LRRK2) to test whether inhibition of LRRK2 kinase activity is a potentially viable treatment option for Parkinson's disease patients. Herein we disclose the use of property and structure-based drug design for the optimization of highly ligand efficient aminopyrimidine lead compds. High throughput in vivo rodent cassette pharmacokinetic studies enabled rapid validation of in vitro-in vivo correlations. Guided by this data, optimal design parameters were established. Effective incorporation of these guidelines into our mol. design process resulted in the discovery of small mol. inhibitors such as GNE-7915 (18, I) and 19, which possess an ideal balance of LRRK2 cellular potency, broad kinase selectivity, metabolic stability, and brain penetration across multiple species. Advancement of GNE-7915 into rodent and higher species toxicity studies enabled risk assessment for early development.
- 234Henderson, J. L.; Kormos, B. L.; Hayward, M. M.; Coffman, K. J.; Jasti, J.; Kurumbail, R. G.; Wager, T. T.; Verhoest, P. R.; Noell, G. S.; Chen, Y.; Needle, E.; Berger, Z.; Steyn, S. J.; Houle, C.; Hirst, W. D.; Galatsis, P. Discovery and preclinical profiling of 3-[4-(morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475), a highly potent, selective, brain penetrant, and in vivo active LRRK2 kinase inhibitor. J. Med. Chem. 2015, 58, 419– 432, DOI: 10.1021/jm5014055[ACS Full Text], [CAS], Google Scholar234https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVens7%252FO&md5=d970c348ae4ec899b504e28060b21f13Discovery and Preclinical Profiling of 3-[4-(Morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475), a Highly Potent, Selective, Brain Penetrant, and in Vivo Active LRRK2 Kinase InhibitorHenderson, Jaclyn L.; Kormos, Bethany L.; Hayward, Matthew M.; Coffman, Karen J.; Jasti, Jayasankar; Kurumbail, Ravi G.; Wager, Travis T.; Verhoest, Patrick R.; Noell, G. Stephen; Chen, Yi; Needle, Elie; Berger, Zdenek; Steyn, Stefanus J.; Houle, Christopher; Hirst, Warren D.; Galatsis, PaulJournal of Medicinal Chemistry (2015), 58 (1), 419-432CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson's disease (PD) by genome-wide assocn. studies (GWAS). The most common LRRK2 mutation, G2019S, which is relatively rare in the total population, gives rise to increased kinase activity. As such, LRRK2 kinase inhibitors are potentially useful in the treatment of PD. We herein disclose the discovery and optimization of a novel series of potent LRRK2 inhibitors, focusing on improving kinome selectivity using a surrogate crystallog. approach. This resulted in the identification of 14 (PF-06447475), a highly potent, brain penetrant and selective LRRK2 inhibitor which has been further profiled in in vivo safety and pharmacodynamic studies.
- 235Williamson, D. S.; Smith, G. P.; Acheson-Dossang, P.; Bedford, S. T.; Chell, V.; Chen, I. J.; Daechsel, J. C. A.; Daniels, Z.; David, L.; Dokurno, P.; Hentzer, M.; Herzig, M. C.; Hubbard, R. E.; Moore, J. D.; Murray, J. B.; Newland, S.; Ray, S. C.; Shaw, T.; Surgenor, A. E.; Terry, L.; Thirstrup, K.; Wang, Y. K.; Christensen, K. V. Design of Leucine-rich repeat kinase 2 (LRRK2) inhibitors using a crystallographic surrogate derived from Checkpoint kinase 1 (CHK1). J. Med. Chem. 2017, 60, 8945– 8962, DOI: 10.1021/acs.jmedchem.7b01186[ACS Full Text], [CAS], Google Scholar235https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1Gms77I&md5=c77bfc36dbd0048d462eaac1531bdc16Design of leucine-rich repeat kinase 2 (LRRK2) inhibitors using a crystallographic surrogate derived from checkpoint kinase 1 (CHK1)Williamson, Douglas S.; Smith, Garrick P.; Acheson-Dossang, Pamela; Bedford, Simon T.; Chell, Victoria; Chen, I-Jen; Daechsel, Justus C. A.; Daniels, Zoe; David, Laurent; Dokurno, Pawel; Hentzer, Morten; Herzig, Martin C.; Hubbard, Roderick E.; Moore, Jonathan D.; Murray, James B.; Newland, Samantha; Ray, Stuart C.; Shaw, Terry; Surgenor, Allan E.; Terry, Lindsey; Thirstrup, Kenneth; Wang, Yikang; Christensen, Kenneth V.Journal of Medicinal Chemistry (2017), 60 (21), 8945-8962CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Mutations in leucine-rich repeat kinase 2 (LRRK2), such as G2019S, are assocd. with an increased risk of developing Parkinson's disease. Surrogates for the LRRK2 kinase domain based on checkpoint kinase 1 (CHK1) mutants were designed, expressed in insect cells infected with baculovirus, purified, and crystd. X-ray structures of the surrogates complexed with known LRRK2 inhibitors rationalized compd. potency and selectivity. The CHK1 10-point mutant was preferred, following assessment of surrogate binding affinity with LRRK2 inhibitors. Fragment hit-derived arylpyrrolo[2,3-b]pyridine LRRK2 inhibitors underwent structure-guided optimization using this crystallog. surrogate. LRRK2-pSer935 HEK293 IC50 data for 22 were consistent with binding to Ala2016 in LRRK2 (equiv. to Ala147 in CHK1 10-point mutant structure). Compd. 22 was shown to be potent, moderately selective, orally available, and brain-penetrant in wild-type mice, and confirmation of target engagement was demonstrated, with LRRK2-pSer935 IC50 values for 22 in mouse brain and kidney being 1.3 and 5 nM, resp.
- 236Scott, J. D.; DeMong, D. E.; Greshock, T. J.; Basu, K.; Dai, X.; Harris, J.; Hruza, A.; Li, S. W.; Lin, S. I.; Liu, H.; Macala, M. K.; Hu, Z.; Mei, H.; Zhang, H.; Walsh, P.; Poirier, M.; Shi, Z. C.; Xiao, L.; Agnihotri, G.; Baptista, M. A.; Columbus, J.; Fell, M. J.; Hyde, L. A.; Kuvelkar, R.; Lin, Y.; Mirescu, C.; Morrow, J. A.; Yin, Z.; Zhang, X.; Zhou, X.; Chang, R. K.; Embrey, M. W.; Sanders, J. M.; Tiscia, H. E.; Drolet, R. E.; Kern, J. T.; Sur, S. M.; Renger, J. J.; Bilodeau, M. T.; Kennedy, M. E.; Parker, E. M.; Stamford, A. W.; Nargund, R.; McCauley, J. A.; Miller, M. W. Discovery of a 3-(4-pyrimidinyl) indazole (MLi-2), an orally available and selective Leucine-rich repeat kinase 2 (LRRK2) inhibitor that reduces brain kinase activity. J. Med. Chem. 2017, 60, 2983– 2992, DOI: 10.1021/acs.jmedchem.7b00045[ACS Full Text], [CAS], Google Scholar236https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjsFaltL8%253D&md5=4d18d0d3288d0a9330c385776a9f0b7cDiscovery of a 3-(4-Pyrimidinyl) Indazole (MLi-2), an Orally Available and Selective Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitor that Reduces Brain Kinase ActivityScott, Jack D.; DeMong, Duane E.; Greshock, Thomas J.; Basu, Kallol; Dai, Xing; Harris, Joel; Hruza, Alan; Li, Sarah W.; Lin, Sue-Ing; Liu, Hong; Macala, Megan K.; Hu, Zhiyong; Mei, Hong; Zhang, Honglu; Walsh, Paul; Poirier, Marc; Shi, Zhi-Cai; Xiao, Li; Agnihotri, Gautam; Baptista, Marco A. S.; Columbus, John; Fell, Matthew J.; Hyde, Lynn A.; Kuvelkar, Reshma; Lin, Yinghui; Mirescu, Christian; Morrow, John A.; Yin, Zhizhang; Zhang, Xiaoping; Zhou, Xiaoping; Chang, Ronald K.; Embrey, Mark W.; Sanders, John M.; Tiscia, Heather E.; Drolet, Robert E.; Kern, Jonathan T.; Sur, Sylvie M.; Renger, John J.; Bilodeau, Mark T.; Kennedy, Matthew E.; Parker, Eric M.; Stamford, Andrew W.; Nargund, Ravi; McCauley, John A.; Miller, Michael W.Journal of Medicinal Chemistry (2017), 60 (7), 2983-2992CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Leucine-Rich Repeat Kinase 2 (LRRK2) is a large, multidomain protein which contains a kinase domain and GTPase domain among other regions. Individuals possessing gain of function mutations in the kinase domain such as the most prevalent G2019S mutation have been assocd. with an increased risk for the development of Parkinson's Disease (PD). Given this genetic validation for inhibition of LRRK2 kinase activity as a potential means of effecting disease progression, the team set out to develop LRRK2 inhibitors to test this hypothesis. A high throughput screen of the compd. collection afforded a no. of promising indazole leads which were truncated in order to identify a min. pharmacophore. Further optimization of these indazoles led to the development of MLi-2 I: a potent, highly selective, orally available, brain penetrant inhibitor of LRRK2.
- 237Fuji, R. N.; Flagella, M.; Baca, M.; Baptista, M. A. S.; Brodbeck, J.; Chan, B. K.; Fiske, B. K.; Honigberg, L.; Jubb, A. M.; Katavolos, P.; Lee, D. W.; Lewin-Koh, S. C.; Lin, T.; Liu, X.; Liu, S.; Lyssikatos, J. P.; O’Mahony, J.; Reichelt, M.; Roose-Girma, M.; Sheng, Z.; Sherer, T.; Smith, A.; Solon, M.; Sweeney, Z. K.; Tarrant, J.; Urkowitz, A.; Warming, S.; Yaylaoglu, M.; Zhang, S.; Zhu, H.; Estrada, A. A.; Watts, R. J. Effect of selective LRRK2 kinase inhibition on nonhuman primate lung. Sci. Transl. Med. 2015, 7, 273ra15, DOI: 10.1126/scitranslmed.aaa3634
- 238Qin, Q.; Zhi, L. T.; Li, X. T.; Yue, Z. Y.; Li, G. Z.; Zhang, H. Effects of LRRK2 inhibitors on nigrostriatal dopaminergic neurotransmission. CNS Neurosci. Ther. 2017, 23, 162– 173, DOI: 10.1111/cns.12660[Crossref], [PubMed], [CAS], Google Scholar238https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1WitL0%253D&md5=cab0675b70721325cfcaf3b63178a079Effects of LRRK2 Inhibitors on Nigrostriatal Dopaminergic NeurotransmissionQin, Qi; Zhi, Lian-Teng; Li, Xian-Ting; Yue, Zhen-Yu; Li, Guo-Zhong; Zhang, HuiCNS Neuroscience & Therapeutics (2017), 23 (2), 162-173CODEN: CNTNAB; ISSN:1755-5930. (Wiley-Blackwell)Introduction : Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most prevalent cause of familial and sporadic Parkinson's disease (PD). Because most pathogenic LRRK2 mutations result in enhanced kinase activity, it suggests that LRRK2 inhibitors may serve as a potential treatment for PD. To evaluate whether LRRK2 inhibitors are effective therapies for PD, it is crucial to know whether LRRK2 inhibitors will affect dopaminergic (DAergic) neurotransmission. However, to date, there is no study to investigate the impact of LRRK2 inhibitors on DAergic neurotransmission. Aims : To address this gap in knowledge, we examd. the effects of three types of LRRK2 inhibitors (LRRK2-IN-1, GSK2578215A, and GNE-7915) on dopamine (DA) release in the dorsal striatum using fast-scan cyclic voltammetry and DA neuron firing in the substantia nigra pars compacta (SNpc) using patch clamp in mouse brain slices. Results : We found that LRRK2-IN-1 at a concn. higher than 1 μM causes off-target effects and decreases DA release, whereas GSK2578215A and GNE-7915 do not. All three inhibitors at 1 μM have no effect on DA release and DA neuron firing rate. We have further assessed the effects of the inhibitors in two preclin. LRRK2 mouse models (i.e., BAC transgenic hG2019S and hR1441G) and demonstrated that GNE-7915 enhances DA release and synaptic vesicle mobilization/recycling. Conclusion : GNE-7915 can be validated for further therapeutic development for PD.
- 239Ishimoto, T.; Lanaspa, M. A.; Rivard, C. J.; Roncal-Jimenez, C. A.; Orlicky, D. J.; Cicerchi, C.; McMahan, R. H.; Abdelmalek, M. F.; Rosen, H. R.; Jackman, M. R.; MacLean, P. S.; Diggle, C. P.; Asipu, A.; Inaba, S.; Kosugi, T.; Sato, W.; Maruyama, S.; Sanchez-Lozada, L. G.; Sautin, Y. Y.; Hill, J. O.; Bonthron, D. T.; Johnson, R. J. High-fat and high-sucrose (western) diet induces steatohepatitis that is dependent on fructokinase. Hepatology 2013, 58, 1632– 1643, DOI: 10.1002/hep.26594[Crossref], [PubMed], [CAS], Google Scholar239https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslWqsLvE&md5=d4544aba25dd28f735c4e0b76e02cc48High-fat and high-sucrose (western) diet induces steatohepatitis that is dependent on fructokinaseIshimoto, Takuji; Lanaspa, Miguel A.; Rivard, Christopher J.; Roncal-Jimenez, Carlos A.; Orlicky, David J.; Cicerchi, Christina; McMahan, Rachel H.; Abdelmalek, Manal F.; Rosen, Hugo R.; Jackman, Matthew R.; MacLean, Paul S.; Diggle, Christine P.; Asipu, Aruna; Inaba, Shinichiro; Kosugi, Tomoki; Sato, Waichi; Maruyama, Shoichi; Sanchez-Lozada, Laura G.; Sautin, Yuri Y.; Hill, James O.; Bonthron, David T.; Johnson, Richard J.Hepatology (Hoboken, NJ, United States) (2013), 58 (5), 1632-1643CODEN: HPTLD9; ISSN:0270-9139. (John Wiley & Sons, Inc.)Fructose intake from added sugars has been implicated as a cause of nonalcoholic fatty liver disease. Here we tested the hypothesis that fructose may interact with a high-fat diet to induce fatty liver, and to det. if this was dependent on a key enzyme in fructose metab., fructokinase. Wild-type or fructokinase knockout mice were fed a low-fat (11%), high-fat (36%), or high-fat (36%) and high-sucrose (30%) diet for 15 wk. Both wild-type and fructokinase knockout mice developed obesity with mild hepatic steatosis and no evidence of hepatic inflammation on a high-fat diet compared to a low-fat diet. In contrast, wild-type mice fed a high-fat and high-sucrose diet developed more severe hepatic steatosis with low-grade inflammation and fibrosis, as noted by increased CD68, tumor necrosis factor alpha, monocyte chemoattractant protein-1, alpha-smooth muscle actin, and collagen I and TIMP1 expression. These changes were prevented in the fructokinase knockout mice. Conclusion: An additive effect of high-fat and high-sucrose diet on the development of hepatic steatosis exists. Further, the combination of sucrose with high-fat diet may induce steatohepatitis. The protection in fructokinase knockout mice suggests a key role for fructose (from sucrose) in this development of steatohepatitis. These studies emphasize the important role of fructose in the development of fatty liver and nonalcoholic steatohepatitis. (Hepatol. 2013;58:1632-1643).
- 240Gibbs, A. C.; Abad, M. C.; Zhang, X.; Tounge, B. A.; Lewandowski, F. A.; Struble, G. T.; Sun, W.; Sui, Z.; Kuo, L. C. Electron density guided fragment-based lead discovery of ketohexokinase inhibitors. J. Med. Chem. 2010, 53, 7979– 7991, DOI: 10.1021/jm100677s[ACS Full Text], [CAS], Google Scholar240https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtlGntr%252FF&md5=3abdf4ac63d4afcf6a4db484d0d87259Electron Density Guided Fragment-Based Lead Discovery of Ketohexokinase InhibitorsGibbs, Alan C.; Abad, Marta C.; Zhang, Xuqing; Tounge, Brett A.; Lewandowski, Francis A.; Struble, Geoffrey T.; Sun, Weimei; Sui, Zhihua; Kuo, Lawrence C.Journal of Medicinal Chemistry (2010), 53 (22), 7979-7991CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A fragment-based drug design paradigm has been successfully applied in the discovery of lead series of ketohexokinase inhibitors. The paradigm consists of three iterations of design, synthesis, and x-ray crystallog. screening to progress low mol. wt. fragments to leadlike compds. Applying electron d. of fragments within the protein binding site as defined by x-ray crystallog., one can generate target specific leads without the use of affinity data. Our approach contrasts with most fragment-based drug design methodol. where soln. activity is a main design guide. Herein we describe the discovery of submicromolar ketohexokinase inhibitors with promising druglike properties.
- 241Huard, K.; Ahn, K.; Amor, P.; Beebe, D. A.; Borzilleri, K. A.; Chrunyk, B. A.; Coffey, S. B.; Cong, Y.; Conn, E. L.; Culp, J. S.; Dowling, M. S.; Gorgoglione, M. F.; Gutierrez, J. A.; Knafels, J. D.; Lachapelle, E. A.; Pandit, J.; Parris, K. D.; Perez, S.; Pfefferkorn, J. A.; Price, D. A.; Raymer, B.; Ross, T. T.; Shavnya, A.; Smith, A. C.; Subashi, T. A.; Tesz, G. J.; Thuma, B. A.; Tu, M.; Weaver, J. D.; Weng, Y.; Withka, J. M.; Xing, G.; Magee, T. V. Discovery of fragment-derived small molecules for in vivo inhibition of Ketohexokinase (KHK). J. Med. Chem. 2017, 60, 7835– 7849, DOI: 10.1021/acs.jmedchem.7b00947[ACS Full Text], [CAS], Google Scholar241https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsVagu7jK&md5=d83bc39986e54a0f41e8f310b725ab92Discovery of Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK)Huard, Kim; Ahn, Kay; Amor, Paul; Beebe, David A.; Borzilleri, Kris A.; Chrunyk, Boris A.; Coffey, Steven B.; Cong, Yang; Conn, Edward L.; Culp, Jeffrey S.; Dowling, Matthew S.; Gorgoglione, Matthew F.; Gutierrez, Jemy A.; Knafels, John D.; Lachapelle, Erik A.; Pandit, Jayvardhan; Parris, Kevin D.; Perez, Sylvie; Pfefferkorn, Jeffrey A.; Price, David A.; Raymer, Brian; Ross, Trenton T.; Shavnya, Andre; Smith, Aaron C.; Subashi, Timothy A.; Tesz, Gregory J.; Thuma, Benjamin A.; Tu, Meihua; Weaver, John D.; Weng, Yan; Withka, Jane M.; Xing, Gang; Magee, Thomas V.Journal of Medicinal Chemistry (2017), 60 (18), 7835-7849CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Increased fructose consumption and its subsequent metab. have been implicated in hepatic steatosis, dyslipidemia, obesity, and insulin resistance in humans. Since ketohexokinase (KHK) is the principal enzyme responsible for fructose metab., identification of a selective KHK inhibitor may help to further elucidate the effect of KHK inhibition on these metabolic disorders. Until now, studies on KHK inhibition with small mols. have been limited due to the lack of viable in vivo pharmacol. tools. Herein the authors report the discovery of 12 (6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-2-((S)-3-hydroxy-3-methylpyrrolidin-1-yl)-4-(trifluoromethyl)nicotinonitrile), a selective KHK inhibitor with potency and properties suitable for evaluating KHK inhibition in rat models. Key structural features interacting with KHK were discovered through fragment-based screening and subsequent optimization using structure-based drug design, and parallel medicinal chem. led to the identification of pyridine 12.
- 242Cannavo, A.; Komici, K.; Bencivenga, L.; D’Amico, M. L.; Gambino, G.; Liccardo, D.; Ferrara, N.; Rengo, G. GRK2 as a therapeutic target for heart failure. Expert Opin. Ther. Targets 2018, 22, 75– 83, DOI: 10.1080/14728222.2018.1406925[Crossref], [PubMed], [CAS], Google Scholar242https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFahtrrM&md5=0727276deb7a0409c71f5bfcf3bcf007GRK2 as a therapeutic target for heart failureCannavo, Alessandro; Komici, Klara; Bencivenga, Leonardo; D'amico, Maria Loreta; Gambino, Giuseppina; Liccardo, Daniela; Ferrara, Nicola; Rengo, GiuseppeExpert Opinion on Therapeutic Targets (2018), 22 (1), 75-83CODEN: EOTTAO; ISSN:1472-8222. (Taylor & Francis Ltd.)A review. G protein-coupled receptor (GPCR) kinase-2 (GRK2) is a regulator of GPCRs, in particular β-adrenergic receptors (ARs), and as demonstrated by decades of investigation, it has a pivotal role in the development and progression of cardiovascular disease, like heart failure (HF). Indeed elevated levels and activity of this kinase are able to promote the dysfunction of both cardiac and adrenal α- and β-ARs and to dysregulate other protective signaling pathway, such as sphingosine 1-phospate and insulin. Moreover, recent discoveries suggest that GRK2 can signal independently from GPCRs, in a 'non-canonical' manner, via interaction with non-GPCR mol. or via its mitochondrial localization. Based on this premise, GRK2 inhibition or its genetic deletion has been tested in several disparate animal models of cardiovascular disease, showing to protect the heart from adverse remodeling and dysfunction. HF is one of the leading cause of death worldwide with enormous health care costs. For this reason, the identification of new therapeutic targets like GRK2 and strategies such as its inhibition represents a new hope in the fight against HF development and progression. Herein, we will update the readers about the 'state-of-art' of GRK2 inhibition as a potent therapeutic strategy in HF.
- 243Eschenhagen, T. β-adrenergic signaling in heart failure-adapt or die. Nat. Med. 2008, 14, 485– 487, DOI: 10.1038/nm0508-485[Crossref], [PubMed], [CAS], Google Scholar243https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXlsFCnu78%253D&md5=116860d5dfec89324c623a51bfe99f89β-adrenergic signaling in heart failure-adapt or dieEschenhagen, ThomasNature Medicine (New York, NY, United States) (2008), 14 (5), 485-487CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)A review. About 25% of the African-American population carries a gene variant that seems to protect against heart failure. The findings may have implications for the use of β-blockers (pages 510-517).
- 244Rockman, H. A.; Chien, K. R.; Choi, D. J.; Iaccarino, G.; Hunter, J. J.; Ross, J., Jr; Lefkowitz, R. J.; Koch, W. J. Expression of a β-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice. Proc. Natl. Acad. Sci. U. S. A. 1998, 95, 7000– 7005, DOI: 10.1073/pnas.95.12.7000[Crossref], [PubMed], [CAS], Google Scholar244https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXjslyms7Y%253D&md5=a456743770d269ba225b206c7657fb6aExpression of a β-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted miceRockman, Howard A.; Chien, Kenneth R.; Choi, Dong-Ju; Iaccarino, Guido; Hunter, John J.; Ross, John, Jr.; Lefkowitz, Robert J.; Koch, Walter J.Proceedings of the National Academy of Sciences of the United States of America (1998), 95 (12), 7000-7005CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Heart failure is accompanied by severely impaired β-adrenergic receptor (βAR) function, which includes loss of βAR d. and functional uncoupling of remaining receptors. An important mechanism for the rapid desensitization of βAR function is agonist-stimulated receptor phosphorylation by the βAR kinase (βARK1), an enzyme known to be elevated in failing human heart tissue. To investigate whether alterations in βAR function contribute to the development of myocardial failure, transgenic mice with cardiac-restricted overexpression of either a peptide inhibitor of βARK1 or the β2AR were mated into a genetic model of murine heart failure (MLP-/-). In vivo cardiac function was assessed by echocardiog. and cardiac catheterization. Both MLP-/- and MLP-/-/β2AR mice had enlarged left ventricular (LV) chambers with significantly reduced fractional shortening and mean velocity of circumferential fiber shortening. In contrast, MLP-/-/βARKct mice had normal LV chamber size and function. Basal LV contractility in the MLP-/-/βARKct mice, as measured by LV dP/dtmax, was increased significantly compared with the MLP-/- mice but less than controls. Importantly, heightened βAR desensitization in the MLP-/- mice, measured in vivo (responsiveness to isoproterenol) and in vitro (isoproterenol-stimulated membrane adenylyl cyclase activity), was completely reversed with overexpression of the βARK1 inhibitor. The authors report here the striking finding that overexpression of this inhibitor prevents the development of cardiomyopathy in this murine model of heart failure. These findings implicate abnormal βAR-G protein coupling in the pathogenesis of the failing heart and point the way toward development of agents to inhibit βARK1 as a novel mode of therapy.
- 245Raake, P. W.; Vinge, L. E.; Gao, E.; Boucher, M.; Rengo, G.; Chen, X.; DeGeorge, B. R., Jr; Matkovich, S.; Houser, S. R.; Most, P.; Eckhart, A. D.; Dorn, G. W., 2nd; Koch, W. J. G protein-coupled receptor kinase 2 ablation in cardiac myocytes before or after myocardial infarction prevents heart failure. Circ. Res. 2008, 103, 413– 422, DOI: 10.1161/CIRCRESAHA.107.168336[Crossref], [PubMed], [CAS], Google Scholar245https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXptlKnurc%253D&md5=2ee73b14bd9dd3db3ec387e5a70ed211G Protein-Coupled Receptor Kinase 2 Ablation in Cardiac Myocytes Before or After Myocardial Infarction Prevents Heart FailureRaake, Philip W.; Vinge, Leif E.; Gao, Erhe; Boucher, Matthieu; Rengo, Giuseppe; Chen, Xiongwen; DeGeorge, Brent R., Jr.; Matkovich, Scot; Houser, Steven R.; Most, Patrick; Eckhart, Andrea D.; Dorn, Gerald W., II; Koch, Walter J.Circulation Research (2008), 103 (4), 413-422CODEN: CIRUAL; ISSN:0009-7330. (Lippincott Williams & Wilkins)Myocardial G protein-coupled receptor kinase (GRK)2 is a crit. regulator of cardiac β-adrenergic receptor (βAR) signaling and cardiac function. Its upregulation in heart failure may further depress cardiac function and contribute to mortality in this syndrome. Preventing GRK2 translocation to activated βAR with a GRK2-derived peptide that binds Gβγ (βARKct) has benefited some models of heart failure, but the precise mechanism is uncertain, because GRK2 is still present and βARKct has other potential effects. We generated mice in which cardiac myocyte GRK2 expression was normal during embryonic development but was ablated after birth (αMHC-Cre×GRK2 fl/fl) or only after administration of tamoxifen (αMHC-MerCreMer×GRK2 fl/fl) and examd. the consequences of GRK2 ablation before and after surgical coronary artery ligation on cardiac adaptation after myocardial infarction. Absence of GRK2 before coronary artery ligation prevented maladaptive postinfarction remodeling and preserved βAR responsiveness. Strikingly, GRK2 ablation initiated 10 days after infarction increased survival, enhanced cardiac contractile performance, and halted ventricular remodeling. These results demonstrate a specific causal role for GRK2 in postinfarction cardiac remodeling and heart failure and support therapeutic approaches of targeting GRK2 or restoring βAR signaling by other means to improve outcomes in heart failure.
- 246Thal, D. M.; Homan, K. T.; Chen, J.; Wu, E. K.; Hinkle, P. M.; Huang, Z. M.; Chuprun, J. K.; Song, J.; Gao, E.; Cheung, J. Y.; Sklar, L. A.; Koch, W. J.; Tesmer, J. J. Paroxetine is a direct inhibitor of g protein-coupled receptor kinase 2 and increases myocardial contractility. ACS Chem. Biol. 2012, 7, 1830– 1839, DOI: 10.1021/cb3003013[ACS Full Text], [CAS], Google Scholar246https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtFOntLfI&md5=08df20fa41a8b3241640db5de557a001Paroxetine Is a Direct Inhibitor of G Protein-Coupled Receptor Kinase 2 and Increases Myocardial ContractilityThal, David M.; Homan, Kristoff T.; Chen, Jun; Wu, Emily K.; Hinkle, Patricia M.; Huang, Z. Maggie; Chuprun, J. Kurt; Song, Jianliang; Gao, Erhe; Cheung, Joseph Y.; Sklar, Larry A.; Koch, Walter J.; Tesmer, John J. G.ACS Chemical Biology (2012), 7 (11), 1830-1839CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)G protein-coupled receptor kinase 2 (GRK2) is a well-established therapeutic target for the treatment of heart failure. Herein we identify the selective serotonin reuptake inhibitor (SSRI) paroxetine as a selective inhibitor of GRK2 activity both in vitro and in living cells. In the crystal structure of the GRK2·paroxetine-Gβγ complex, paroxetine binds in the active site of GRK2 and stabilizes the kinase domain in a novel conformation in which a unique regulatory loop forms part of the ligand binding site. Isolated cardiomyocytes show increased isoproterenol-induced shortening and contraction amplitude in the presence of paroxetine, and pretreatment of mice with paroxetine before isoproterenol significantly increases left ventricular inotropic reserve in vivo with no significant effect on heart rate. Neither is obsd. in the presence of the SSRI fluoxetine. Our structural and functional results validate a widely available drug as a selective chem. probe for GRK2 and represent a starting point for the rational design of more potent and specific GRK2 inhibitors.
- 247Schumacher, S. M.; Gao, E.; Zhu, W.; Chen, X.; Chuprun, J. K.; Feldman, A. M.; Tesmer, J. J. G.; Koch, W. J. Paroxetine-mediated GRK2 inhibition reverses cardiac dysfunction and remodeling after myocardial infarction. Sci. Transl. Med. 2015, 7, 277ra31, DOI: 10.1126/scitranslmed.aaa0154
- 248Guccione, M.; Ettari, R.; Taliani, S.; Da Settimo, F.; Zappala, M.; Grasso, S. G-protein-coupled receptor kinase 2 (GRK2) inhibitors: current trends and future perspectives. J. Med. Chem. 2016, 59, 9277– 9294, DOI: 10.1021/acs.jmedchem.5b01939[ACS Full Text], [CAS], Google Scholar248https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtV2gsL3L&md5=76c06627842335aae6430144d5f03e7aG-Protein-Coupled Receptor Kinase 2 (GRK2) Inhibitors: Current Trends and Future PerspectivesGuccione, Manuela; Ettari, Roberta; Taliani, Sabrina; Da Settimo, Federico; Zappala, Maria; Grasso, SilvanaJournal of Medicinal Chemistry (2016), 59 (20), 9277-9294CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. G-protein-coupled receptor kinase 2 (GRK2) is a G-protein-coupled receptor kinase that is ubiquitously expressed in many tissues and regulates various intracellular mechanisms. The up- or down-regulation of GRK2 correlates with several pathol. disorders. GRK2 plays an important role in the maintenance of heart structure and function; thus, this kinase is involved in many cardiovascular diseases. GRK2 up-regulation can worsen cardiac ischemia; furthermore, increased kinase levels occur during the early stages of heart failure and in hypertensive subjects. GRK2 up-regulation can lead to changes in the insulin signaling cascade, which can translate to insulin resistance. Increased GRK2 levels also correlate with the degree of cognitive impairment that is typically obsd. in Alzheimer's disease. This article reviews the most potent and selective GRK2 inhibitors that have been developed. The authors focus on their mechanism of action, inhibition profile, and structure-activity relationships to provide insight into the further development of GRK2 inhibitors as drug candidates.
- 249Thal, D. M.; Yeow, R. Y.; Schoenau, C.; Huber, J.; Tesmer, J. J. Molecular mechanism of selectivity among G protein-coupled receptor kinase 2 inhibitors. Mol. Pharmacol. 2011, 80, 294– 303, DOI: 10.1124/mol.111.071522[Crossref], [PubMed], [CAS], Google Scholar249https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXps1yqsL0%253D&md5=cde68787c0f4f20131ffe88ddbfd9284Molecular mechanism of selectivity among G protein-coupled receptor kinase 2 inhibitorsThal, David M.; Yeow, Raymond Y.; Schoenau, Christian; Huber, Jochen; Tesmer, John J. G.Molecular Pharmacology (2011), 80 (2), 294-303CODEN: MOPMA3; ISSN:0026-895X. (American Society for Pharmacology and Experimental Therapeutics)G protein-coupled receptors (GPCRs) are key regulators of cell physiol. and control processes ranging from glucose homeostasis to contractility of the heart. A major mechanism for the desensitization of activated GPCRs is their phosphorylation by GPCR kinases (GRKs). Overexpression of GRK2 is strongly linked to heart failure, and GRK2 has long been considered a pharmaceutical target for the treatment of cardiovascular disease. Several lead compds. developed by Takeda Pharmaceuticals show high selectivity for GRK2 and therapeutic potential for the treatment of heart failure. To understand how these drugs achieve their selectivity, we detd. crystal structures of the bovine GRK2-Gβγ complex in the presence of two of these inhibitors. Comparison with the apoGRK2-Gβγ structure demonstrates that the compds. bind in the kinase active site in a manner similar to that of the AGC kinase inhibitor balanol. Both balanol and the Takeda compds. induce a slight closure of the kinase domain, the degree of which correlates with the potencies of the inhibitors. Based on our crystal structures and homol. modeling, we identified five amino acids surrounding the inhibitor binding site that we hypothesized could contribute to inhibitor selectivity. However, our results indicate that these residues are not major determinants of selectivity among GRK subfamilies. Rather, selectivity is achieved by the stabilization of a unique inactive conformation of the GRK2 kinase domain.
- 250Waldschmidt, H. V.; Homan, K. T.; Cruz-Rodriguez, O.; Cato, M. C.; Waninger-Saroni, J.; Larimore, K. M.; Cannavo, A.; Song, J.; Cheung, J. Y.; Kirchhoff, P. D.; Koch, W. J.; Tesmer, J. J.; Larsen, S. D. Structure-based design, synthesis, and biological evaluation of highly selective and potent G protein-coupled receptor kinase 2 inhibitors. J. Med. Chem. 2016, 59, 3793– 3807, DOI: 10.1021/acs.jmedchem.5b02000[ACS Full Text], [CAS], Google Scholar250https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XlsVOgtL8%253D&md5=149b7722909617a88d439ae3d90338a4Structure-Based Design, Synthesis, and Biological Evaluation of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 InhibitorsWaldschmidt, Helen V.; Homan, Kristoff T.; Cruz-Rodriguez, Osvaldo; Cato, Marilyn C.; Waninger-Saroni, Jessica; Larimore, Kelly L.; Cannavo, Alessandro; Song, Jianliang; Cheung, Joseph Y.; Kirchhoff, Paul D.; Koch, Walter J.; Tesmer, John J. G.; Larsen, Scott D.Journal of Medicinal Chemistry (2016), 59 (8), 3793-3807CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)G protein-coupled receptors (GPCRs) are central to many physiol. processes. Regulation of this superfamily of receptors is controlled by GPCR kinases (GRKs), some of which have been implicated in heart failure. GSK180736A, developed as a Rho-assocd. coiled-coil kinase 1 (ROCK1) inhibitor, was identified as an inhibitor of GRK2 and co-crystd. in the active site. Guided by its binding pose overlaid with the binding pose of a known potent GRK2 inhibitor, Takeda103A, a library of hybrid inhibitors was developed. This campaign produced several compds. possessing high potency and selectivity for GRK2 over other GRK subfamilies, PKA, and ROCK1. The most selective compd., 12n (I) (CCG-224406), had an IC50 for GRK2 of 130 nM, >700-fold selectivity over other GRK subfamilies, and no detectable inhibition of ROCK1. Four of the new inhibitors were crystd. with GRK2 to give mol. insights into the binding and kinase selectivity of this class of inhibitors.
- 251Okawa, T.; Aramaki, Y.; Yamamoto, M.; Kobayashi, T.; Fukumoto, S.; Toyoda, Y.; Henta, T.; Hata, A.; Ikeda, S.; Kaneko, M.; Hoffman, I. D.; Sang, B. C.; Zou, H.; Kawamoto, T. Design, synthesis, and evaluation of the highly selective and potent G-protein-coupled receptor kinase 2 (GRK2) inhibitor for the potential treatment of heart failure. J. Med. Chem. 2017, 60, 6942– 6990, DOI: 10.1021/acs.jmedchem.7b00443[ACS Full Text], [CAS], Google Scholar251https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFGitbjF&md5=6077a12ddcbd4454ccfc4d55c65c5a61Design, Synthesis, and Evaluation of the Highly Selective and Potent G-Protein-Coupled Receptor Kinase 2 (GRK2) Inhibitor for the Potential Treatment of Heart FailureOkawa, Tomohiro; Aramaki, Yoshio; Yamamoto, Mitsuo; Kobayashi, Toshitake; Fukumoto, Shoji; Toyoda, Yukio; Henta, Tsutomu; Hata, Akito; Ikeda, Shota; Kaneko, Manami; Hoffman, Isaac D.; Sang, Bi-Ching; Zou, Hua; Kawamoto, TetsujiJournal of Medicinal Chemistry (2017), 60 (16), 6942-6990CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A novel class of therapeutic drug candidates for heart failure, highly potent and selective GRK2 inhibitors, exhibit potentiation of β-adrenergic signaling in vitro studies. Hydrazone deriv. and 1,2,4-triazole deriv. were identified as hit compds. by HTS. New scaffold generation and SAR studies of all parts resulted in a 4-methyl-1,2,4-triazole deriv. with an N-benzylcarboxamide moiety with highly potent activity towards GRK2, and selectivity over other kinases. In terms of subtype selectivity, these compds. showed enough selectivity against GRK1, 5, 6, 7 with almost equipotent inhibition to GRK3. The medicinal chem. efforts led to the discovery of I (GRK2 IC50 = 18 nM) which was obtained the cocrystal structure with human GRK2 and an inhibitor of GRK2 that potentiates β-adrenergic receptor (βAR)-mediated cAMP accumulation and prevents internalization of βARs in β2AR-expressing HEK293 cells treated with isoproterenol. Therefore, I appears to be a novel class of therapeutic for heart failure treatment.
- 252Razani, B.; Reichardt, A. D.; Cheng, G. Non-canonical NF-κB signaling activation and regulation: principles and perspectives. Immunol Rev. 2011, 244, 44– 54, DOI: 10.1111/j.1600-065X.2011.01059.x[Crossref], [PubMed], [CAS], Google Scholar252https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFagsL%252FK&md5=b4b7e40a5437602ea0a61aaa5577e1f3Non-canonical NF-κB signaling activation and regulation: principles and perspectivesRazani, Bahram; Reichardt, Anna Devi; Cheng, GenhongImmunological Reviews (2011), 244 (1), 44-54CODEN: IMRED2; ISSN:1600-065X. (Wiley-Blackwell)A review. Nuclear-factor κB (NF-κB) transcription factors are activated by a wide variety of stimuli in diverse cell types and control key aspects of immune function and development. Receptor-mediated activation of NF-κB appears to occur through two distinct signaling pathways termed as the canonical and non-canonical NF-κB pathways. Although much work has demonstrated the physiol. importance of non-canonical NF-κB signaling to immunity and its involvement in diverse pathologies, such as cancers and autoimmune disease, the architecture and regulation of the pathway is only beginning to be understood. The non-canonical pathway appears to be activated by a select set of receptors within the tumor necrosis factor superfamily, and we discuss the mol. mechanisms that connect ligation of these receptors to pathway activation. It has become increasingly clear that the key regulatory step of the pathway involves modulation of the post-translational degrdn. of NF-κB-inducing kinase (NIK), the central activating kinase of non-canonical NF-κB signaling. How NIK post-translational stability is controlled before and after receptor ligation is an important aspect of understanding non-canonical NF-κB signaling. Furthermore, how release of NF-κB dimers downstream of the pathway's activation is actually connected to its identified physiol. and pathol. roles is a key remaining question in the field.
- 253Ren, X.; Li, X.; Jia, L.; Chen, D.; Hou, H.; Rui, L.; Zhao, Y.; Chen, Z. A small-molecule inhibitor of NF-κB-inducing kinase (NIK) protects liver from toxin-induced inflammation, oxidative stress, and injury. FASEB J. 2017, 31, 711– 718, DOI: 10.1096/fj.201600840R[Crossref], [PubMed], [CAS], Google Scholar253https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXpsleit78%253D&md5=84f05fa8fdf2fcfe79d167827ceea738A small-molecule inhibitor of NF-κB-inducing kinase (NIK) protects liver from toxin-induced inflammation, oxidative stress, and injuryRen, Xiaomeng; Li, Xinzhi; Jia, Linna; Chen, Deheng; Hou, Hai; Rui, Liangyou; Zhao, Yujun; Chen, ZhengFASEB Journal (2017), 31 (2), 711-718CODEN: FAJOEC; ISSN:0892-6638. (Federation of American Societies for Experimental Biology)Potent and selective chem. probes are valuable tools for discovery of novel treatments for human diseases. NF-κB-inducing kinase (NIK) is a key trigger in the development of liver injury and fibrosis. Whether inhibition of NIK activity by chem. probes ameliorates liver inflammation and injury is largely unknown. In this study, a small-mol. inhibitor of NIK, B022, was found to be a potent and selective chem. probe for liver inflammation and injury. B022 inhibited the NIK signaling pathway, including NIK-induced p100-to-p52 processing and inflammatory gene expression, both in vitro and in vivo. Furthermore, in vivo administration of B022 protected against not only NIK but also CCl4-induced liver inflammation and injury. Our data suggest that inhibition of NIK is a novel strategy for treatment of liver inflammation, oxidative stress, and injury.
- 254Castanedo, G. M.; Blaquiere, N.; Beresini, M.; Bravo, B.; Brightbill, H.; Chen, J.; Cui, H. F.; Eigenbrot, C.; Everett, C.; Feng, J.; Godemann, R.; Gogol, E.; Hymowitz, S.; Johnson, A.; Kayagaki, N.; Kohli, P. B.; Knuppel, K.; Kraemer, J.; Kruger, S.; Loke, P.; McEwan, P.; Montalbetti, C.; Roberts, D. A.; Smith, M.; Steinbacher, S.; Sujatha-Bhaskar, S.; Takahashi, R.; Wang, X.; Wu, L. C.; Zhang, Y.; Staben, S. T. Structure-based design of tricyclic NF-κB inducing kinase (NIK) inhibitors that have high selectivity over Phosphoinositide-3-kinase (PI3K). J. Med. Chem. 2017, 60, 627– 640, DOI: 10.1021/acs.jmedchem.6b01363[ACS Full Text], [CAS], Google Scholar254https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitFCgs7bK&md5=316b70f51a5b800ba810082d0b3862daStructure-Based Design of Tricyclic NF-κB Inducing Kinase (NIK) Inhibitors That Have High Selectivity over Phosphoinositide-3-kinase (PI3K)Castanedo, Georgette M.; Blaquiere, Nicole; Beresini, Maureen; Bravo, Brandon; Brightbill, Hans; Chen, Jacob; Cui, Hai-Feng; Eigenbrot, Charles; Everett, Christine; Feng, Jianwen; Godemann, Robert; Gogol, Emily; Hymowitz, Sarah; Johnson, Adam; Kayagaki, Nobuhiko; Kohli, Pawan Bir; Knuppel, Kathleen; Kraemer, Joachim; Kruger, Susan; Loke, Pui; McEwan, Paul; Montalbetti, Christian; Roberts, David A.; Smith, Myron; Steinbacher, Stefan; Sujatha-Bhaskar, Swathi; Takahashi, Ryan; Wang, Xiaolu; Wu, Lawren C.; Zhang, Yamin; Staben, Steven T.Journal of Medicinal Chemistry (2017), 60 (2), 627-640CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The authors report a structure-guided optimization of a novel series of NF-κB inducing kinase (NIK) inhibitors. Starting from a modestly potent, low mol. wt. lead, activity was improved by designing a type I1/2 binding mode that accessed a back pocket past the methionine-471 gatekeeper. Divergent binding modes in NIK and PI3K were used to dampen PI3K-inhibition while maintaining NIK inhibition within these series. Potent compds. were discovered that selectively inhibit the nuclear translocation of NF-kB2 (p52/REL-B) but not canonical NF-kB1 (REL-A/p50).
- 255Blaquiere, N.; Castanedo, G. M.; Burch, J. D.; Berezhkovskiy, L. M.; Brightbill, H.; Brown, S.; Chan, C.; Chiang, P. C.; Crawford, J. J.; Dong, T.; Fan, P.; Feng, J.; Ghilardi, N.; Godemann, R.; Gogol, E.; Grabbe, A.; Hole, A. J.; Hu, B.; Hymowitz, S. G.; Alaoui Ismaili, M. H.; Le, H.; Lee, P.; Lee, W.; Lin, X.; Liu, N.; McEwan, P. A.; McKenzie, B.; Silvestre, H. L.; Suto, E.; Sujatha-Bhaskar, S.; Wu, G.; Wu, L. C.; Zhang, Y.; Zhong, Z.; Staben, S. T. Scaffold-hopping approach to discover potent, selective, and efficacious inhibitors of NF-κB inducing kinase. J. Med. Chem. 2018, 61, 6801– 6813, DOI: 10.1021/acs.jmedchem.8b00678[ACS Full Text], [CAS], Google Scholar255https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXht1Snu73P&md5=5ff01b23d827b3d96078a17fff885aeaScaffold-Hopping Approach To Discover Potent, Selective, and Efficacious Inhibitors of NF-κB Inducing KinaseBlaquiere, Nicole; Castanedo, Georgette M.; Burch, Jason D.; Berezhkovskiy, Leonid M.; Brightbill, Hans; Brown, Suzanne; Chan, Connie; Chiang, Po-Chang; Crawford, James J.; Dong, Teresa; Fan, Peter; Feng, Jianwen; Ghilardi, Nico; Godemann, Robert; Gogol, Emily; Grabbe, Alice; Hole, Alison J.; Hu, Baihua; Hymowitz, Sarah G.; Alaoui Ismaili, Moulay Hicham; Le, Hoa; Lee, Patrick; Lee, Wyne; Lin, Xingyu; Liu, Ning; McEwan, Paul A.; McKenzie, Brent; Silvestre, Hernani L.; Suto, Eric; Sujatha-Bhaskar, Swathi; Wu, Guosheng; Wu, Lawren C.; Zhang, Yamin; Zhong, Zoe; Staben, Steven T.Journal of Medicinal Chemistry (2018), 61 (15), 6801-6813CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)NF-κB-inducing kinase (NIK) is a protein kinase central to the noncanonical NF-κB pathway downstream from multiple TNF receptor family members, including BAFF, which has been assocd. with B cell survival and maturation, dendritic cell activation, secondary lymphoid organ development, and bone metab. We report herein the discovery of lead chem. series of NIK inhibitors that were identified through a scaffold-hopping strategy using structure-based design. Electronic and steric properties of lead compds. were modified to address glutathione conjugation and amide hydrolysis. These highly potent compds. exhibited selective inhibition of LTβR-dependent p52 translocation and transcription of NF-κB2 related genes. Compd. 4f is shown to have a favorable pharmacokinetic profile across species and to inhibit BAFF-induced B cell survival in vitro and reduce splenic marginal zone B cells in vivo.
- 256Brightbill, H. D.; Suto, E.; Blaquiere, N.; Ramamoorthi, N.; Sujatha-Bhaskar, S.; Gogol, E. B.; Castanedo, G. M.; Jackson, B. T.; Kwon, Y. C.; Haller, S.; Lesch, J.; Bents, K.; Everett, C.; Kohli, P. B.; Linge, S.; Christian, L.; Barrett, K.; Jaochico, A.; Berezhkovskiy, L. M.; Fan, P. W.; Modrusan, Z.; Veliz, K.; Townsend, M. J.; DeVoss, J.; Johnson, A. R.; Godemann, R.; Lee, W. P.; Austin, C. D.; McKenzie, B. S.; Hackney, J. A.; Crawford, J. J.; Staben, S. T.; Alaoui Ismaili, M. H.; Wu, L. C.; Ghilardi, N. NF-κB inducing kinase is a therapeutic target for systemic lupus erythematosus. Nat. Commun. 2018, 9, 179, DOI: 10.1038/s41467-017-02672-0[Crossref], [PubMed], [CAS], Google Scholar256https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1Mvgtlylug%253D%253D&md5=41a91514e1f4e8b2b44912ba6d6a4788NF-κB inducing kinase is a therapeutic target for systemic lupus erythematosusBrightbill Hans D; Sujatha-Bhaskar Swathi; Gogol Emily B; Jackson Benjamin T; Christian Laura; Wu Lawren C; Ghilardi Nico; Suto Eric; Kwon Youngsu C; Lesch Justin; DeVoss Jason; Lee Wyne P; McKenzie Brent S; Blaquiere Nicole; Castanedo Georgette M; Crawford James J; Staben Steven T; Ramamoorthi Nandhini; Townsend Michael J; Haller Susan; Austin Cary D; Bents Karin; Linge Sandra; Godemann Robert; Everett Christine; Kohli Pawan Bir; Barrett Kathy; Johnson Adam R; Alaoui Ismaili Moulay H; Jaochico Allan; Berezhkovskiy Leonid M; Fan Peter W; Modrusan Zora; Veliz Kelli; Hackney Jason ANature communications (2018), 9 (1), 179 ISSN:.NF-κB-inducing kinase (NIK) mediates non-canonical NF-κB signaling downstream of multiple TNF family members, including BAFF, TWEAK, CD40, and OX40, which are implicated in the pathogenesis of systemic lupus erythematosus (SLE). Here, we show that experimental lupus in NZB/W F1 mice can be treated with a highly selective and potent NIK small molecule inhibitor. Both in vitro as well as in vivo, NIK inhibition recapitulates the pharmacological effects of BAFF blockade, which is clinically efficacious in SLE. Furthermore, NIK inhibition also affects T cell parameters in the spleen and proinflammatory gene expression in the kidney, which may be attributable to inhibition of OX40 and TWEAK signaling, respectively. As a consequence, NIK inhibition results in improved survival, reduced renal pathology, and lower proteinuria scores. Collectively, our data suggest that NIK inhibition is a potential therapeutic approach for SLE.
- 257Zhu, Y.; Ma, Y.; Zu, W.; Song, J.; Wang, H.; Zhong, Y.; Li, H.; Zhang, Y.; Gao, Q.; Kong, B.; Xu, J.; Jiang, F.; Wang, X.; Li, S.; Liu, C.; Liu, H.; Lu, T.; Chen, Y. Identification of N-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine derivatives as novel, potent, and selective NF-κB inducing kinase (NIK) inhibitors for the treatment of psoriasis. J. Med. Chem. 2020, 63, 6748– 6773, DOI: 10.1021/acs.jmedchem.0c00055[ACS Full Text], [CAS], Google Scholar257https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtVKnt7vN&md5=159d4bb74b1d7c3111aaa55cba35f64cIdentification of N-Phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine Derivatives as Novel, Potent, and Selective NF-κB Inducing Kinase (NIK) Inhibitors for the Treatment of PsoriasisZhu, Yuqin; Ma, Yuxiang; Zu, Weidong; Song, Jianing; Wang, Hua; Zhong, You; Li, Hongmei; Zhang, Yanmin; Gao, Qianqian; Kong, Bo; Xu, Junyu; Jiang, Fei; Wang, Xinren; Li, Shuwen; Liu, Chenhe; Liu, Haichun; Lu, Tao; Chen, YadongJournal of Medicinal Chemistry (2020), 63 (13), 6748-6773CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of N-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine derivs. with NF-κB inducing kinase (NIK) inhibitory activity were obtained through structure-based drug design and synthetic chem. Among them, 4-(3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4-morpholinophenyl)-2-(thiazol-2-yl)but-3-yn-2-ol (12f)(I) was identified as a highly potent NIK inhibitor, along with satisfactory selectivity. The pharmacokinetics of 12f and its ability to inhibit interleukin 6 secretion in BEAS-2B cells were better than compd. 1 developed by Amgen. Oral administration of different doses of 12f in an imiquimod-induced psoriasis mouse model showed effective alleviation of psoriasis, including invasive erythema, swelling, skin thickening, and scales. The underlying pathol. mechanism involved attenuation of proinflammatory cytokine and chemokine gene expression, and the infiltration of macrophages after the treatment of 12f. This work provides a foundation for the development of NIK inhibitors, highlighting the potential of developing NIK inhibitors as a new strategy for the treatment of psoriasis.
- 258Li, Z.; Li, X.; Su, M. B.; Gao, L. X.; Zhou, Y. B.; Yuan, B.; Lyu, X.; Yan, Z.; Hu, C.; Zhang, H.; Luo, C.; Chen, Z.; Li, J.; Zhao, Y. Discovery of a potent and selective NF-κB-inducing kinase (NIK) inhibitor that has anti-inflammatory effects in vitro and in vivo. J. Med. Chem. 2020, 63, 4388– 4407, DOI: 10.1021/acs.jmedchem.0c00396[ACS Full Text], [CAS], Google Scholar258https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXlvVGmt74%253D&md5=40edf4070f12b964303d3ed8e72dad9fDiscovery of a Potent and Selective NF-κB-Inducing Kinase (NIK) Inhibitor That Has Anti-inflammatory Effects in Vitro and in VivoLi, Zhiqiang; Li, Xinzhi; Su, Ming-Bo; Gao, Li-Xin; Zhou, Yu-Bo; Yuan, Bingchuan; Lyu, Xilin; Yan, Ziqin; Hu, Chujiao; Zhang, Hao; Luo, Cheng; Chen, Zheng; Li, Jia; Zhao, YujunJournal of Medicinal Chemistry (2020), 63 (8), 4388-4407CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The overexpression of NIK plays a crit. role in liver inflammatory diseases. Treatment of such diseases with small-mol. NIK inhibitors is a reasonable but underexplored approach. In this paper, we reported the discovery of a potent and selective NIK inhibitor 46 (XT2). 46 inhibited the NIK kinase with an IC50 value of 9.1 nM in vitro, and it also potently suppressed NIK activities in intact cells. In isogenic primary hepatocytes, treatment of 46 efficiently suppressed the expressions of NIK-induced genes. 46 was orally bioavailable in mice with moderate systemic exposure. In a NIK-assocd. mouse liver inflammation model, 46 suppressed CCl4-induced upregulation of ALT, a key biomarker of acute liver injury. 46 also decreased immune cell infiltration into the injured liver tissue. Overall, these studies provide examples that an NIK inhibitor is able to suppress toxin-induced liver inflammations, which indicates its therapeutic potentials for the treatment of liver inflammatory diseases.
- 259Liao, C.; Yao, R. S. Diversity evolution and jump of Polo-like kinase 1 inhibitors. Sci. China: Chem. 2013, 56, 1392– 1401, DOI: 10.1007/s11426-013-4963-0[Crossref], [CAS], Google Scholar259https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtlCqsrfJ&md5=3c43ec202554cda7cf7114fa07ac84aeDiversity evolution and jump of Polo-like kinase 1 inhibitorsLiao, Chenzhong; Yao, Ri ShengScience China: Chemistry (2013), 56 (10), 1392-1401CODEN: SCCCCS; ISSN:1869-1870. (Science China Press)A review. Polo-like kinase 1 (Plk1), a member of a family of serine/threonine kinases, is an attractive target for the development of anticancer drugs because it is involved in the regulation of cell-cycle progression and cytokinesis. This kinase provides two pockets for developing Plk1 inhibitors: the N-terminal catalytic domain (NCD) and the polo-box domain (PBD). For both of the two pockets, some natural products were identified as Plk1 inhibitors and some synthetic Plk1 inhibitors were developed by mimicking ATP and phosphopeptides, natural products binding to NCD and PBD resp. This article not only reviews the progression of Plk1 inhibitors binding to these two pockets, but also discusses diversity evolution and jump in the process of drug development using Plk1 inhibitors as examples and how they impact on drug design and pharmacophore modeling.
- 260Lv, X.; Yang, X.; Zhan, M. M.; Cao, P.; Zheng, S.; Peng, R.; Han, J.; Xie, Z.; Tu, Z.; Liao, C. Structure-based design and SAR development of novel selective polo-like kinase 1 inhibitors having the tetrahydropteridin scaffold. Eur. J. Med. Chem. 2019, 184, 111769, DOI: 10.1016/j.ejmech.2019.111769[Crossref], [PubMed], [CAS], Google Scholar260https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvF2rsbzN&md5=bd6caed64a3e9587a7dc670888a4c521Structure-based design and SAR development of novel selective polo-like kinase 1 inhibitors having the tetrahydropteridin scaffoldLv, Xiao; Yang, Xiaoxiao; Zhan, Mei-Miao; Cao, Peichang; Zheng, Shihong; Peng, Ruijun; Han, Jihong; Xie, Zhouling; Tu, Zhengchao; Liao, ChenzhongEuropean Journal of Medicinal Chemistry (2019), 184 (), 111769CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)Polo-like kinase 1 (Plk1) is a validated target for the treatment of cancer. In this report, by analyzing amino acid residue differences among the ATP-binding pockets of Plk1, Plk2 and Plk3, novel selective Plk1 inhibitors were designed based on BI 2536 and BI 6727, two Plk1 inhibitors in clin. studies for cancer treatments. The Plk1 inhibitors reported herein have more potent inhibition against Plk1 and better isoform selectivity in the Plk family than these two lead compds. In addn., by introducing a hydroxyl group, our compds. have significantly improved soly. and may target specific polar residues Arg57, Glu69 and Arg134 of Plk1. Moreover, most of our compds. exhibited antitumor activities in the nanomolar range against several cancer cell lines in the MTT assay. Through this structure-based design strategy and SAR study, a few promising selective Plk1 inhibitors having the tetrahydropteridin scaffold, for example, L34(I), were identified and could be for further anticancer research.
- 261Huang, X.; Xie, Z.; Liao, C. Developing polo-like kinase 1 inhibitors. Future Med. Chem. 2020, 12, 869– 871, DOI: 10.4155/fmc-2020-0055[Crossref], [PubMed], [CAS], Google Scholar261https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXpslygtro%253D&md5=da8b26c3c3205058cf25b5203e4802e9Developing polo-like kinase 1 inhibitorsHuang, Xufeng; Xie, Zhouling; Liao, ChenzhongFuture Medicinal Chemistry (2020), 12 (10), 869-871CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)There is no expanded citation for this reference.
- 262Cozza, G.; Salvi, M. The acidophilic kinases PLK2 and PLK3: structure, substrate targeting and inhibition. Curr. Protein Pept. Sci. 2018, 19, 728– 745, DOI: 10.2174/1389203719666180124095405[Crossref], [PubMed], [CAS], Google Scholar262https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXht1yku7rK&md5=97cbaf75a8ae18438b30485bafd712faThe Acidophilic Kinases PLK2 and PLK3: Structure, Substrate Targeting and InhibitionCozza, Giorgio; Salvi, MauroCurrent Protein and Peptide Science (2018), 19 (8), 728-745CODEN: CPPSCM; ISSN:1389-2037. (Bentham Science Publishers Ltd.)A review. PLK2 and PLK3 are two closely related acidophilic kinases belonging to the Polo-like kinases (PLKs), a family of five members in mammals with a central role in cell cycle and related events. PLK1 is the most investigated enzyme from both physiol. and pharmaceutical points of view, however, several specialized cellular functions of PLK2 and PLK3 have been recently discovered paving the way to deepened studies on their biol. roles and their feasible selection as future therapeutic targets. Our review aims to provide a summarized view of the current knowledge regarding PLK2 and PLK3 kinases, including substrate specificity and signaling pathways directly affected by these kinases. Finally, an overview of PLK2 and PLK3 pharmacol. regulation and perspectives in future achievements are proposed.
- 263Hu, Z.; Xu, Z.; Liao, X.; Yang, X.; Dong, C.; Luk, K.; Jin, A.; Lu, H. Polo-like kinase 2 acting as a promoter in human tumor cells with an abundance of TAp73. OncoTargets Ther. 2015, 8, 3475– 3488, DOI: 10.2147/OTT.S90302[Crossref], [PubMed], [CAS], Google Scholar263https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXls1yms7c%253D&md5=0b0d456be9526a4b1b4ecdd42a49cd1bPolo-like kinase 2 acting as a promoter in human tumor cells with an abundance of TAp73 ZhengBo Hu1,* ZunYing Xu1,* XiaoHongHu, Zheng Bo; Xu, Zun Ying; Liao, Xiao Hong; Yang, Xiao; Dong, Cao; Luk, Kua Di; Jin, An Min; Lu, HaiOncoTargets and Therapy (2015), 8 (), 3475-3488CODEN: OTNHAZ; ISSN:1178-6930. (Dove Medical Press Ltd.)Background: TAp73, a member of the p53 tumor suppressor family, is frequently overexpressed in malignant tumors in humans. TAp73 abundance and phosphorylation modification result in variations in transcriptional activity. In a previous study, we found that the antitumor function of TAp73 was reactivated by dephosphorylation in head and neck squamous cell carcinomas. Polo-like kinase 2 (PLK2) displayed a close relationship with the p53 family in affecting the fate of cells. Herein, we investigate the hypothesis that PLK2 phosphorylates TAp73 and inhibits TAp73 function. Materials and methods: Head and neck squamous cell carcinoma cell lines and osteosarcoma cell lines were used as natural models of the different expression levels of TAp73. Phosphorylation predictor software Scansite 3.0 and the predictor GPS-polo 1.0 were used to analyze the phosphorylation sites. Coimmunopptn., phosphor-tag Western blot, metabolic labeling, and indirect immunofluorescence assays were used to det. the interactions between PLK2 and TAp73. TAp73 activity was assessed by Western blot and reverse transcription polymerase chain reaction, which we used to detect P21 and PUMA, both downstream genes of TAp73. The physiol. effects of PLK2 cross talk with TAp73 on cell cycle progress and apoptosis were obsd. by flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling assays. Results: PLK2 binds to and phosphorylates TAp73. PLK2 phosphorylates TAp73 at residue Ser48 and prohibits TAp73 translocation to the nucleus. Addnl., PLK2 inhibition combined with a DNA-damaging drug upregulated p21 and PUMA mRNA expression to a greater extent than DNA-damaging drug treatment alone. Inhibiting PLK2 in TAp73-enriched cells strengthened the effects of the DNA-damaging drug on both G1 phase arrest and apoptosis. Pretreatment with TAp73-siRNA weakened these effects. Conclusion: These findings reveal a novel PLK2 function (catalyzed phosphorylation of TAp73) which suppresses TAp73 functions. PLK2 promotes the survival of human tumor cells, a novel insight into the workings of malignant tumors characterized by TAp73 overexpression, and one that could speed the development of therapies.
- 264Zhan, M. M.; Yang, Y.; Luo, J.; Zhang, X. X.; Xiao, X.; Li, S.; Cheng, K.; Xie, Z.; Tu, Z.; Liao, C. Design, synthesis, and biological evaluation of novel highly selective polo-like kinase 2 inhibitors based on the tetrahydropteridin chemical scaffold. Eur. J. Med. Chem. 2018, 143, 724– 731, DOI: 10.1016/j.ejmech.2017.11.058[Crossref], [PubMed], [CAS], Google Scholar264https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFejt7jJ&md5=833fc543d15f8d79752cfb37975920d3Design, synthesis, and biological evaluation of novel highly selective polo-like kinase 2 inhibitors based on the tetrahydropteridin chemical scaffoldZhan, Mei-Miao; Yang, Yang; Luo, Jinfeng; Zhang, Xing-Xing; Xiao, Xuan; Li, Shiyu; Cheng, Kai; Xie, Zhouling; Tu, Zhengchao; Liao, ChenzhongEuropean Journal of Medicinal Chemistry (2018), 143 (), 724-731CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)Aminosulfonylphenylamino- and indolyl-substituted tetrahydropteridines such as I were prepd. as selective inhibitors of Polo-like kinase 2 (Plk2) for potential use as antitumor agents. The inhibition of Plk2 and of the related enzymes Plk1 and Plk3 of aminosulfonylphenylamino- and indolyl-substituted tetrahydropteridines and their inhibition of human cancer cell lines was detd.; mol. docking calcns. of selected compds. in the active site of Plk2 were performed. A (methylaminosulfonylphenylamino)tetrahydropteridine (IC50 for Plk2 = 3.40 nM) and I (IC50 for Plk2 = 4.88 nM) were identified as the most active Plk2 inhibitors; I was 12-fold and >900-fold selective for Plk2 over Plk1 and Plk3, resp.
- 265Kofoed, R. H.; Zheng, J.; Ferreira, N.; Lykke-Andersen, S.; Salvi, M.; Betzer, C.; Reimer, L.; Jensen, T. H.; Fog, K.; Jensen, P. H. Polo-like kinase 2 modulates α-synuclein protein levels by regulating its mRNA production. Neurobiol. Dis. 2017, 106, 49– 62, DOI: 10.1016/j.nbd.2017.06.014[Crossref], [PubMed], [CAS], Google Scholar265https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVKntL7F&md5=f68095edcbd07c21522b1ead6f096788Polo-like kinase 2 modulates α-synuclein protein levels by regulating its mRNA productionKofoed, Rikke H.; Zheng, Jin; Ferreira, Nelson; Lykke-Andersen, Soeren; Salvi, Mauro; Betzer, Cristine; Reimer, Lasse; Jensen, Torben Heick; Fog, Karina; Jensen, Poul H.Neurobiology of Disease (2017), 106 (), 49-62CODEN: NUDIEM; ISSN:0969-9961. (Elsevier Inc.)Variations in the α-synuclein-encoding SNCA gene represent the greatest genetic risk factor for Parkinson's disease (PD), and duplications/triplications of SNCA cause autosomal dominant familial PD. These facts closely link brain levels of α-synuclein with the risk of PD, and make lowering α-synuclein levels a therapeutic strategy for the treatment of PD and related synucleinopathies. In this paper, we corroborate previous findings on the ability of overexpressed Polo-like kinase 2 (PLK-2) to decrease cellular α-synuclein, but demonstrate that the process is independent of PLK-2 phosphorylating S129 in α-synuclein because a similar redn. is achieved with the non-phosphorable S129A mutant α-synuclein. Using a specific PLK-2 inhibitor (compd. 37), we demonstrate that endogenous PLK-2 phosphorylates S129 only in some cells, but increases α-synuclein protein levels in all tested cell cultures and brain slices. PLK-2 is found to regulate the transcription of α-synuclein mRNA from both the endogenous mouse SNCA gene and transgenic vectors that only contain the open reading frame. Moreover, we are the first to show that regulation of α-synuclein by PLK-2 is of physiol. importance since 10 days' inhibition of endogenous PLK-2 in wt C57BL/6 mice increases endogenous α-synuclein protein levels. Our findings collectively demonstrate that PLK-2 regulates α-synuclein levels by a previously undescribed transcription-based mechanism. This mechanism is active in cells and brain tissue, opening up for alternative strategies for modulating α-synuclein levels and thereby for the possibility of modifying disease progression in synucleinopaties.
- 266Aubele, D. L.; Hom, R. K.; Adler, M.; Galemmo, R. A.; Bowers, S.; Truong, A. P.; Pan, H.; Beroza, P.; Neitz, R. J.; Yao, N. H.; Lin, M.; Tonn, G.; Zhang, H.; Bova, M. P.; Ren, Z.; Tam, D.; Ruslim, L.; Baker, J.; Diep, L.; Fitzgerald, K.; Hoffman, J.; Motter, R.; Fauss, D.; Tanaka, P.; Dappen, M.; Jagodzinski, J.; Chan, W. M.; Konradi, A. W.; Latimer, L.; Zhu, Y. L.; Sham, H. L.; Anderson, J. P.; Bergeron, M.; Artis, D. R. Selective and brain-permeable Polo-like kinase-2 (Plk-2) inhibitors that reduce -synuclein phosphorylation in rat brain. ChemMedChem 2013, 8, 1295– 1313, DOI: 10.1002/cmdc.201300166[Crossref], [PubMed], [CAS], Google Scholar266https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXpvVensLY%253D&md5=3f5d2981036f440498862c2c85199083Selective and Brain-Permeable Polo-like Kinase-2 (Plk-2) Inhibitors That Reduce α-Synuclein Phosphorylation in Rat BrainAubele, Danielle L.; Hom, Roy K.; Adler, Marc; Galemmo, Robert A., Jr.; Bowers, Simeon; Truong, Anh P.; Pan, Hu; Beroza, Paul; Neitz, R. Jeffrey; Yao, Nanhua; Lin, May; Tonn, George; Zhang, Heather; Bova, Michael P.; Ren, Zhao; Tam, Danny; Ruslim, Lany; Baker, Jeanne; Diep, Linnea; Fitzgerald, Kent; Hoffman, Jennifer; Motter, Ruth; Fauss, Donald; Tanaka, Pearl; Dappen, Michael; Jagodzinski, Jacek; Chan, Wayman; Konradi, Andrei W.; Latimer, Lee; Zhu, Yong L.; Sham, Hing L.; Anderson, John P.; Bergeron, Marcelle; Artis, Dean R.ChemMedChem (2013), 8 (8), 1295-1313CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)Polo-like kinase-2 (Plk-2) has been implicated as the dominant kinase involved in the phosphorylation of α-synuclein in Lewy bodies, which are one of the hallmarks of Parkinson's disease neuropathol. Potent, selective, brain-penetrant inhibitors of Plk-2 were obtained from a structure-guided drug discovery approach driven by the first reported Plk-2-inhibitor complexes. The best of these compds. showed excellent isoform and kinome-wide selectivity, with physicochem. properties sufficient to interrogate the role of Plk-2 inhibition in vivo. One such compd. significantly decreased phosphorylation of α-synuclein in rat brain upon oral administration and represents a useful probe for future studies of this therapeutic avenue toward the potential treatment of Parkinson's disease.
- 267Fitzgerald, K.; Bergeron, M.; Willits, C.; Bowers, S.; Aubele, D. L.; Goldbach, E.; Tonn, G.; Ness, D.; Olaharski, A. Pharmacological inhibition of polo like kinase 2 (PLK2) does not cause chromosomal damage or result in the formation of micronuclei. Toxicol. Appl. Pharmacol. 2013, 269, 1– 7, DOI: 10.1016/j.taap.2013.02.012[Crossref], [PubMed], [CAS], Google Scholar267https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXlvVCnu7g%253D&md5=853686e26e5f21cce4adac193a8198f2Pharmacological inhibition of Polo Like Kinase 2 (PLK2) does not cause chromosomal damage or result in the formation of micronucleiFitzgerald, Kent; Bergeron, Marcelle; Willits, Christopher; Bowers, Simeon; Aubele, Danielle L.; Goldbach, Erich; Tonn, George; Ness, Daniel; Olaharski, AndrewToxicology and Applied Pharmacology (2013), 269 (1), 1-7CODEN: TXAPA9; ISSN:0041-008X. (Elsevier Inc.)Polo Like Kinase 2 (PLK2) phosphorylates α-synuclein and is considered a putative therapeutic target for Parkinson's disease. Several lines of evidence indicate that PLK2 is involved with proper centriole duplication and cell cycle regulation, inhibition of which could impact chromosomal integrity during mitosis. The objectives of the series of expts. presented herein were to assess whether specific inhibition of PLK2 is genotoxic and det. if PLK2 could be considered a tractable pharmacol. target for Parkinson's disease. Several selective PLK2 inhibitors, ELN 582175 and ELN 582646, and their inactive enantiomers, ELN 582176 and ELN 582647, did not significantly increase the no. of micronuclei in the in vitro micronucleus assay. ELN 582646 was administered to male Sprague Dawley rats in an exploratory 14-day study where flow cytometric anal. of peripheral blood identified a dose-dependent increase in the no. of micronucleated reticulocytes. A follow-up investigative study demonstrated that ELN 582646 administered to PLK2 deficient and wildtype mice significantly increased the no. of peripheral micronucleated reticulocytes in both genotypes, suggesting that ELN 582646-induced genotoxicity is not through the inhibition of PLK2. Furthermore, significant redn. of retinal phosphorylated α-synuclein levels was obsd. at three non-genotoxic doses, addnl. data to suggest that pharmacol. inhibition of PLK2 is not the cause of the obsd. genotoxicity. These data, in aggregate, indicate that PLK2 inhibition is a tractable CNS pharmacol. target that does not cause genotoxicity at doses and exposures that engage the target in the sensory retina.
- 268Steegmaier, M.; Hoffmann, M.; Baum, A.; Lenart, P.; Petronczki, M.; Krssak, M.; Gurtler, U.; Garin-Chesa, P.; Lieb, S.; Quant, J.; Grauert, M.; Adolf, G. R.; Kraut, N.; Peters, J. M.; Rettig, W. J. BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo. Curr. Biol. 2007, 17, 316– 322, DOI: 10.1016/j.cub.2006.12.037[Crossref], [PubMed], [CAS], Google Scholar268https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhvVyjtbg%253D&md5=49807e335b4ab8cf8209b55597fc7b4eBI 2536, a Potent and Selective Inhibitor of Polo-like Kinase 1, Inhibits Tumor Growth In VivoSteegmaier, Martin; Hoffmann, Matthias; Baum, Anke; Lenart, Peter; Petronczki, Mark; Krssak, Martin; Guertler, Ulrich; Garin-Chesa, Pilar; Lieb, Simone; Quant, Jens; Grauert, Matthias; Adolf, Guenther R.; Kraut, Norbert; Peters, Jan-Michael; Rettig, Wolfgang J.Current Biology (2007), 17 (4), 316-322CODEN: CUBLE2; ISSN:0960-9822. (Cell Press)Fine-mapping of the cell-division cycle, notably the identification of mitotic kinase signaling pathways, provides novel opportunities for cancer-drug discovery. As a key regulator of multiple steps during mitotic progression across eukaryotic species, the serine/threonine-specific Polo-like kinase 1 (Plk1) is highly expressed in malignant cells and serves as a neg. prognostic marker in specific human cancer types . Here, we report the discovery of a potent small-mol. inhibitor of mammalian Plk1, BI 2536, which inhibits Plk1 enzyme activity at low nanomolar concns. The compd. potently causes a mitotic arrest and induces apoptosis in human cancer cell lines of diverse tissue origin and oncogenome signature. BI 2536 inhibits growth of human tumor xenografts in nude mice and induces regression of large tumors with well-tolerated i.v. dose regimens. In treated tumors, cells arrest in prometaphase, accumulate phosphohistone H3, and contain aberrant mitotic spindles. This mitotic arrest is followed by a surge in apoptosis, detectable by immunohistochem. and noninvasive optical and magnetic resonance imaging. For addressing the therapeutic potential of Plk1 inhibition, BI 2536 has progressed into clin. studies in patients with locally advanced or metastatic cancers.
- 269Cabrera, D. G.; Horatscheck, A.; Wilson, C. R.; Basarab, G.; Eyermann, C. J.; Chibale, K. Plasmodial kinase inhibitors: license to cure?. J. Med. Chem. 2018, 61, 8061– 8077, DOI: 10.1021/acs.jmedchem.8b00329[ACS Full Text], [CAS], Google Scholar269https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXps12ltrg%253D&md5=274df0d629d4cf4fcb7a158e9e72aaabPlasmodial Kinase Inhibitors: License to Cure?Cabrera, Diego Gonzalez; Horatscheck, Andre; Wilson, Colin R.; Basarab, Greg; Eyermann, Charles J.; Chibale, KellyJournal of Medicinal Chemistry (2018), 61 (18), 8061-8077CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Advances in the genetics, function, and stage-specificity of Plasmodium kinases has driven robust efforts to identify targets for the design of antimalarial therapies. Reverse genomics following phenotypic screening against Plasmodia or related parasites has uncovered vulnerable kinase targets including PI4K, PKG, and GSK-3, an approach bolstered by access to human disease-directed kinase libraries. Alternatively, screening compd. libraries against Plasmodium kinases has successfully led to inhibitors with antiplasmodial activity. As with other therapeutic areas, optimizing compd. ADMET and PK properties in parallel with target inhibitory potency and whole cell activity becomes paramount toward advancing compds. as clin. candidates. These and other considerations will be discussed in the context of progress achieved toward deriving important, novel mode-of-action kinase-inhibiting antimalarial medicines.
- 270McNamara, C. W.; Lee, M. C.; Lim, C. S.; Lim, S. H.; Roland, J.; Simon, O.; Yeung, B. K.; Chatterjee, A. K.; McCormack, S. L.; Manary, M. J.; Zeeman, A. M.; Dechering, K. J.; Kumar, T. S.; Henrich, P. P.; Gagaring, K.; Ibanez, M.; Kato, N.; Kuhen, K. L.; Fischli, C.; Nagle, A.; Rottmann, M.; Plouffe, D. M.; Bursulaya, B.; Meister, S.; Rameh, L.; Trappe, J.; Haasen, D.; Timmerman, M.; Sauerwein, R. W.; Suwanarusk, R.; Russell, B.; Renia, L.; Nosten, F.; Tully, D. C.; Kocken, C. H.; Glynne, R. J.; Bodenreider, C.; Fidock, D. A.; Diagana, T. T.; Winzeler, E. A. Targeting Plasmodium PI(4)K to eliminate malaria. Nature 2013, 504, 248– 253, DOI: 10.1038/nature12782[Crossref], [PubMed], [CAS], Google Scholar270https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFaqsLzP&md5=9ed8f3e41d257bb4535b4c813abd54cfTargeting Plasmodium PI(4)K to eliminate malariaMcNamara, Case W.; Lee, Marcus C. S.; Lim, Chek Shik; Lim, Siau Hoi; Roland, Jason; Nagle, Advait; Simon, Oliver; Yeung, Bryan K. S.; Chatterjee, Arnab K.; McCormack, Susan L.; Manary, Micah J.; Zeeman, Anne-Marie; Dechering, Koen J.; Kumar, T. R. Santha; Henrich, Philipp P.; Gagaring, Kerstin; Ibanez, Maureen; Kato, Nobutaka; Kuhen, Kelli L.; Fischli, Christoph; Rottmann, Matthias; Plouffe, David M.; Bursulaya, Badry; Meister, Stephan; Rameh, Lucia; Trappe, Joerg; Haasen, Dorothea; Timmerman, Martijn; Sauerwein, Robert W.; Suwanarusk, Rossarin; Russell, Bruce; Renia, Laurent; Nosten, Francois; Tully, David C.; Kocken, Clemens H. M.; Glynne, Richard J.; Bodenreider, Christophe; Fidock, David A.; Diagana, Thierry T.; Winzeler, Elizabeth A.Nature (London, United Kingdom) (2013), 504 (7479), 248-253CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here the authors identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compd. class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax, and inhibit liver-stage hypnozoites in the simian parasite P. cynomolgi. The authors show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate. Collectively, the authors' data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria.
- 271Bozdech, Z.; Ferreira, P. E.; Mok, S. A crucial piece in the puzzle of the artemisinin resistance mechanism in Plasmodium falciparum. Trends Parasitol. 2015, 31, 345– 346, DOI: 10.1016/j.pt.2015.06.004[Crossref], [PubMed], [CAS], Google Scholar271https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFWgsbvO&md5=42949da3589ee312e5f0e74ba2819c75A crucial piece in the puzzle of the artemisinin resistance mechanism in Plasmodium falciparumBozdech, Zbynek; Ferreira, Pedro E.; Mok, SachelTrends in Parasitology (2015), 31 (8), 345-346CODEN: TPRACT; ISSN:1471-4922. (Elsevier Ltd.)The spread of resistance of malaria infections to artemisinin is a major concern for the future. The Plasmodium falciparum phosphatidylinositol-3-kinase (PfPI3K) may be a potential target of artemisinin and effector of resistance. This could be mediated by the Kelch13 protein, the mol. marker of resistance that modulates PfPI3K ubiquitination.
- 272Younis, Y.; Douelle, F.; Feng, T. S.; Cabrera, D. G.; Le Manach, C.; Nchinda, A. T.; Duffy, S.; White, K. L.; Shackleford, D. M.; Morizzi, J.; Mannila, J.; Katneni, K.; Bhamidipati, R.; Zabiulla, K. M.; Joseph, J. T.; Bashyam, S.; Waterson, D.; Witty, M. J.; Hardick, D.; Wittlin, S.; Avery, V.; Charman, S. A.; Chibale, K. 3,5-diaryl-2-aminopyridines as a novel class of orally active antimalarials demonstrating single dose cure in mice and clinical candidate potential. J. Med. Chem. 2012, 55, 3479– 3487, DOI: 10.1021/jm3001373[ACS Full Text], [CAS], Google Scholar272https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjt1SqtL4%253D&md5=6f8bd20049550b82b81b3c7c5b0b9aae3,5-Diaryl-2-aminopyridines as a Novel Class of Orally Active Antimalarials Demonstrating Single Dose Cure in Mice and Clinical Candidate PotentialYounis, Yassir; Douelle, Frederic; Feng, Tzu-Shean; Cabrera, Diego Gonzalez; Manach, Claire Le; Nchinda, Aloysius T.; Duffy, Sandra; White, Karen L.; Shackleford, David M.; Morizzi, Julia; Mannila, Janne; Katneni, Kasiram; Bhamidipati, Ravi; Zabiulla, K. Mohammed; Joseph, Jayan T.; Bashyam, Sridevi; Waterson, David; Witty, Michael J.; Hardick, David; Wittlin, Sergio; Avery, Vicky; Charman, Susan A.; Chibale, KellyJournal of Medicinal Chemistry (2012), 55 (7), 3479-3487CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A novel class of orally active antimalarial 3,5-diaryl-2-aminopyridines has been identified from phenotypic whole cell high-throughput screening of a com. available SoftFocus kinase library. The compds. were evaluated in vitro for their antiplasmodial activity against K1 (chloroquine and drug-resistant strain) and NF54 (chloroquine-susceptible strain) as well as for their cytotoxicity. Synthesis and structure-activity studies identified a no. of promising compds. with selective antiplasmodial activity. One of these front-runner compds., I, was equipotent across the two strains (K1 = 25.0 nM, NF54 = 28.0 nM) and superior to chloroquine in the K1 strain (chloroquine IC50 K1 = 194.0 nM). Compd. I completely cured Plasmodium berghei-infected mice with a single oral dose of 30 mg/kg. Dose-response studies generated ED50 and ED90 values of 0.83 and 1.74 mg/kg for 15 in the std. four-dose Peters test. Pharmacokinetic studies in the rat indicated that I has good oral bioavailability (51% at 20 mg/kg) and a reasonable half-life (t1/2 ∼ 7-8 h).
- 273Droucheau, E.; Primot, A.; Thomas, V.; Mattei, D.; Knockaert, M.; Richardson, C.; Sallicandro, P.; Alano, P.; Jafarshad, A.; Baratte, B.; Kunick, C.; Parzy, D.; Pearl, L.; Doerig, C.; Meijer, L. Plasmodium falciparum glycogen synthase kinase-3: molecular model, expression, intracellular localisation and selective inhibitors. Biochim. Biophys. Acta, Proteins Proteomics 2004, 1697, 181– 196, DOI: 10.1016/j.bbapap.2003.11.023[Crossref], [PubMed], [CAS], Google Scholar273https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXitFKlsLw%253D&md5=d7a7289b294d3cb46d28c122bb7e7e5ePlasmodium falciparum glycogen synthase kinase-3: molecular model, expression, intracellular localization and selective inhibitorsDroucheau, Eliane; Primot, Aline; Thomas, Virginie; Mattei, Denise; Knockaert, Marie; Richardson, Chris; Sallicandro, Pina; Alano, Pietro; Jafarshad, Ali; Baratte, Blandine; Kunick, Conrad; Parzy, Daniel; Pearl, Laurence; Doerig, Christian; Meijer, LaurentBiochimica et Biophysica Acta, Proteins and Proteomics (2004), 1697 (1-2), 181-196CODEN: BBAPBW; ISSN:1570-9639. (Elsevier B.V.)A review. Worldwide increasing resistance of Plasmodium falciparum to common antimalarias calls for the urgent identification of new drugs. Glycogen synthase kinase-3 (GSK-3) represents a potential screening target for the identification of such new compds. The authors have cloned PfGSK-3, the P. falciparum gene homolog of GSK-3β. It encodes a 452-amino-acid, 53-kDa protein with an unusual N-terminal extension but a well-conserved catalytic domain. A PfGSK-3 tridimensional homol. model was generated on the basis of the recently crystd. human GSK-3β. It illustrates how the regions involved in the active site, in substrate binding (P+4 phosphate-binding domain) and in activity regulation are highly conserved. Recombinant PfGSK-3 phosphorylates GS-1, a GSK-3-specific peptide substrate, glycogen synthase, recombinant axin, and microtubule-binding protein tau. Neither native nor recombinant PfGSK-3 binds to axin. The expression and intracellular localization of PfGSK-3 have been investigated in the erythrocytic stages. Although PfGSK-3 mRNA is present in similar amts. at all stages, the PfGSK-3 protein is predominantly expressed at the early trophozoite stage. Once synthesized, PfGSK-3 is rapidly transported to the erythrocyte cytoplasm where it assocs. with vesicle-like structures. The physiol. functions of PfGSK-3 for the parasite remain to be elucidated. A series of GSK-3β inhibitors have been tested on both PfGSK-3 and mammalian GSK-3β. Remarkably, these enzymes have shown a partially divergent sensitivity to the compds., suggesting that PfGSK-3 selective compds. might be identified.
- 274Fugel, W.; Oberholzer, A. E.; Gschloessl, B.; Dzikowski, R.; Pressburger, N.; Preu, L.; Pearl, L. H.; Baratte, B.; Ratin, M.; Okun, I.; Doerig, C.; Kruggel, S.; Lemcke, T.; Meijer, L.; Kunick, C. 3,6-Diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitriles are selective inhibitors of Plasmodium falciparum glycogen synthase kinase-3. J. Med. Chem. 2013, 56, 264– 275, DOI: 10.1021/jm301575n[ACS Full Text], [CAS], Google Scholar274https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhsl2lsrzL&md5=841d254e2f6c6e7a62c947f82fabd0923,6-Diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitriles Are Selective Inhibitors of Plasmodium falciparum Glycogen Synthase Kinase-3Fugel, Wiebke; Oberholzer, Anselm Erich; Gschloessl, Bernhard; Dzikowski, Ron; Pressburger, Narkiss; Preu, Lutz; Pearl, Laurence H.; Baratte, Blandine; Ratin, Morgane; Okun, Ilya; Doerig, Christian; Kruggel, Sebastian; Lemcke, Thomas; Meijer, Laurent; Kunick, ConradJournal of Medicinal Chemistry (2013), 56 (1), 264-275CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Plasmodium falciparum is the infective agent responsible for malaria tropica. The glycogen synthase kinase-3 of the parasite (PfGSK-3) was suggested as a potential biol. target for novel antimalarial drugs. Starting from hit structures identified in a high-throughput screening campaign, 3,6-diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitriles, e.g. I, were discovered as a new class of PfGSK-3 inhibitors. Being less active on GSK-3 homologues of other species, the title compds. showed selectivity in favor of PfGSK-3. Taking into account the X-ray structure of a related mol. in complex with human GSK-3 (HsGSK-3), a model was computed for the comparison of inhibitor complexes with the plasmodial and human enzymes. It was found that subtle differences in the ATP-binding pockets are responsible for the obsd. PfGSK-3 vs HsGSK-3 selectivity. Representatives of the title compd. class exhibited micromolar IC50 values against P. falciparum erythrocyte stage parasites. These results suggest that inhibitors of PfGSK-3 could be developed as potential antimalarial drugs.
- 275Alam, M. M.; Sanchez-Azqueta, A.; Janha, O.; Flannery, E. L.; Mahindra, A.; Mapesa, K.; Char, A. B.; Sriranganadane, D.; Brancucci, N. M. B.; Antonova-Koch, Y.; Crouch, K.; Simwela, N. V.; Millar, S. B.; Akinwale, J.; Mitcheson, D.; Solyakov, L.; Dudek, K.; Jones, C.; Zapatero, C.; Doerig, C.; Nwakanma, D. C.; Vazquez, M. J.; Colmenarejo, G.; Lafuente-Monasterio, M. J.; Leon, M. L.; Godoi, P. H. C.; Elkins, J. M.; Waters, A. P.; Jamieson, A. G.; Alvaro, E. F.; Ranford-Cartwright, L. C.; Marti, M.; Winzeler, E. A.; Gamo, F. J.; Tobin, A. B. Validation of the protein kinase PfCLK3 as a multistage cross-species malarial drug target. Science 2019, 365, eaau1682 DOI: 10.1126/science.aau1682
- 276Chapman, T. M.; Osborne, S. A.; Wallace, C.; Birchall, K.; Bouloc, N.; Jones, H. M.; Ansell, K. H.; Taylor, D. L.; Clough, B.; Green, J. L.; Holder, A. A. Optimization of an imidazopyridazine series of inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1). J. Med. Chem. 2014, 57, 3570– 3587, DOI: 10.1021/jm500342d[ACS Full Text], [CAS], Google Scholar276https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXltF2rtLs%253D&md5=4aa3206475bb43f750477da00f9a66b6Optimization of an Imidazopyridazine Series of Inhibitors of Plasmodium falciparum Calcium-Dependent Protein Kinase 1 (PfCDPK1)Chapman, Timothy M.; Osborne, Simon A.; Wallace, Claire; Birchall, Kristian; Bouloc, Nathalie; Jones, Hayley M.; Ansell, Keith H.; Taylor, Debra L.; Clough, Barbara; Green, Judith L.; Holder, Anthony A.Journal of Medicinal Chemistry (2014), 57 (8), 3570-3587CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A structure-guided design approach using a homol. model of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1) was used to improve the potency of a series of imidazopyridazine inhibitors as potential antimalarial agents. This resulted in high affinity compds. with PfCDPK1 enzyme IC50 values less than 10 nM and in vitroP. falciparum antiparasite EC50 values down to 12 nM, although these compds. did not have suitable ADME properties to show in vivo efficacy in a mouse model. Structural modifications designed to address the ADME issues, in particular permeability, were initially accompanied by losses in antiparasite potency, but further optimization allowed a good balance in the compd. profile to be achieved. Upon testing in vivo in a murine model of efficacy against malaria, high levels of compd. exposure relative to their in vitro activities were achieved, and the modest efficacy that resulted raises questions about the level of effect that is achievable through the targeting of PfCDPK1.
- 277Ojo, K. K.; Eastman, R. T.; Vidadala, R.; Zhang, Z.; Rivas, K. L.; Choi, R.; Lutz, J. D.; Reid, M. C.; Fox, A. M.; Hulverson, M. A.; Kennedy, M.; Isoherranen, N.; Kim, L. M.; Comess, K. M.; Kempf, D. J.; Verlinde, C. L.; Su, X. Z.; Kappe, S. H.; Maly, D. J.; Fan, E.; Van Voorhis, W. C. A specific inhibitor of PfCDPK4 blocks malaria transmission: chemical-genetic validation. J. Infect. Dis. 2014, 209, 275– 284, DOI: 10.1093/infdis/jit522[Crossref], [PubMed], [CAS], Google Scholar277https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXit1Smtg%253D%253D&md5=cc5499eca2d177bfa8cb1c523eb54525A Specific Inhibitor of PfCDPK4 Blocks Malaria Transmission: Chemical-genetic ValidationOjo, Kayode K.; Eastman, Richard T.; Vidadala, Rama Subba Rao; Zhang, Zhongsheng; Rivas, Kasey L.; Choi, Ryan; Lutz, Justin D.; Reid, Molly C.; Fox, Anna M. W.; Hulverson, Matthew A.; Kennedy, Mark; Isoherranen, Nina; Kim, Laura M.; Comess, Kenneth M.; Kempf, Dale J.; Verlinde, Christophe L. M. J.; Su, Xin-zhuan; Kappe, Stefan H. I.; Maly, Dustin J.; Fan, Erkang; Van Voorhis, Wesley C.Journal of Infectious Diseases (2014), 209 (2), 275-284CODEN: JIDIAQ; ISSN:0022-1899. (Oxford University Press)Malaria parasites are transmitted by mosquitoes, and blocking parasite transmission is crit. in reducing or eliminating malaria in endemic regions. Here, we report the pharmacol. characterization of a new class of malaria transmission-blocking compds. that acts via the inhibition of Plasmodia CDPK4 enzyme. We demonstrate that these compds. achieved selectivity over mammalian kinases by capitalizing on a small serine gatekeeper residue in the active site of the Plasmodium CDPK4 enzyme. To directly confirm the mechanism of action of these compds., we generated P. falciparum parasites that express a drug-resistant methionine gatekeeper (S147M) CDPK4 mutant. Mutant parasites showed a shift in exflagellation EC50 relative to the wild-type strains in the presence of compd. 1294, providing chem.-genetic evidence that CDPK4 is the target of the compd. Pharmacokinetic analyses suggest that coformulation of this transmission-blocking agent with asexual stage antimalarials such as artemisinin combination therapy (ACT) is a promising option for drug delivery that may reduce transmission of malaria including drug-resistant strains. Ongoing studies include refining the compds. to improve efficacy and toxicol. properties for efficient blocking of malaria transmission.
- 278Baker, D. A.; Stewart, L. B.; Large, J. M.; Bowyer, P. W.; Ansell, K. H.; Jimenez-Diaz, M. B.; El Bakkouri, M.; Birchall, K.; Dechering, K. J.; Bouloc, N. S.; Coombs, P. J.; Whalley, D.; Harding, D. J.; Smiljanic-Hurley, E.; Wheldon, M. C.; Walker, E. M.; Dessens, J. T.; Lafuente, M. J.; Sanz, L. M.; Gamo, F. J.; Ferrer, S. B.; Hui, R.; Bousema, T.; Angulo-Barturen, I.; Merritt, A. T.; Croft, S. L.; Gutteridge, W. E.; Kettleborough, C. A.; Osborne, S. A. A potent series targeting the malarial cGMP-dependent protein kinase clears infection and blocks transmission. Nat. Commun. 2017, 8, 430, DOI: 10.1038/s41467-017-00572-x[Crossref], [PubMed], [CAS], Google Scholar278https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cbkvF2rtg%253D%253D&md5=3b6f60a0c537ab7295a82f8a8f551ff4A potent series targeting the malarial cGMP-dependent protein kinase clears infection and blocks transmissionBaker David A; Stewart Lindsay B; Bowyer Paul W; Walker Eloise M; Dessens Johannes T; Croft Simon L; Gutteridge Winston E; Large Jonathan M; Ansell Keith H; Birchall Kristian; Bouloc Nathalie S; Coombs Peter J; Whalley David; Harding Denise J; Smiljanic-Hurley Ela; Wheldon Mary C; Merritt Andy T; Kettleborough Catherine A; Osborne Simon A; Jimenez-Diaz Maria B; Lafuente Maria Jose; Sanz Laura M; Gamo Francisco-Javier; Ferrer Santiago B; Angulo-Barturen Inigo; El Bakkouri Majida; Hui Raymond; El Bakkouri Majida; Hui Raymond; Dechering Koen J; Bousema TeunNature communications (2017), 8 (1), 430 ISSN:.To combat drug resistance, new chemical entities are urgently required for use in next generation anti-malarial combinations. We report here the results of a medicinal chemistry programme focused on an imidazopyridine series targeting the Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG). The most potent compound (ML10) has an IC50 of 160 pM in a PfPKG kinase assay and inhibits P. falciparum blood stage proliferation in vitro with an EC50 of 2.1 nM. Oral dosing renders blood stage parasitaemia undetectable in vivo using a P. falciparum SCID mouse model. The series targets both merozoite egress and erythrocyte invasion, but crucially, also blocks transmission of mature P. falciparum gametocytes to Anopheles stephensi mosquitoes. A co-crystal structure of PvPKG bound to ML10, reveals intimate molecular contacts that explain the high levels of potency and selectivity we have measured. The properties of this series warrant consideration for further development to produce an antimalarial drug.Protein kinases are promising drug targets for treatment of malaria. Here, starting with a medicinal chemistry approach, Baker et al. generate an imidazopyridine that selectively targets Plasmodium falciparum PKG, inhibits blood stage parasite growth in vitro and in mice and blocks transmission to mosquitoes.
- 279Milne, G.; Webster, J. P.; Walker, M. Toxoplasma gondii: an underestimated threat?. Trends Parasitol. 2020, 36, 959, DOI: 10.1016/j.pt.2020.08.005[Crossref], [PubMed], [CAS], Google Scholar279https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3s%252FntFSnsA%253D%253D&md5=5d22c9a0b770752d1ac9126a0909ca6dToxoplasma gondii: AnUnderestimated Threat?Milne Gregory; Webster Joanne P; Walker MartinTrends in parasitology (2020), 36 (12), 959-969 ISSN:.Traditionally, the protozoan parasite Toxoplasma gondii has been thought of as relevant to public health primarily within the context of congenital toxoplasmosis or postnatally acquired disease in immunocompromised patients. However, latent T.gondii infection has been increasingly associated with a wide variety of neuropsychiatric disorders and, more recently, causal frameworks for these epidemiological associations have been proposed. We present assimilated evidence on the associations between T.gondii and various human neuropsychiatric disorders and outline how these may be explained within a unifying causal framework. We argue that the occult effects of latent T.gondii infection likely outweigh the recognised overt morbidity caused by toxoplasmosis, substantially raising the public health importance of this parasite.
- 280Lourido, S.; Shuman, J.; Zhang, C.; Shokat, K. M.; Hui, R.; Sibley, L. D. Calcium-dependent protein kinase 1 is an essential regulator of exocytosis in Toxoplasma. Nature 2010, 465, 359– 362, DOI: 10.1038/nature09022[Crossref], [PubMed], [CAS], Google Scholar280https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmt1Oisr0%253D&md5=750f6bf5c933759605574d4a2ab5acccCalcium-dependent protein kinase 1 is an essential regulator of exocytosis in ToxoplasmaLourido, Sebastian; Shuman, Joel; Zhang, Chao; Shokat, Kevan M.; Hui, Raymond; Sibley, L. DavidNature (London, United Kingdom) (2010), 465 (7296), 359-362CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Calcium-regulated exocytosis is a ubiquitous process in eukaryotes, whereby secretory vesicles fuse with the plasma membrane and release their contents in response to an intracellular calcium surge. This process regulates various cellular functions such as plasma membrane repair in plants and animals, the discharge of defensive spikes in Paramecium, and the secretion of insulin from pancreatic cells, immune modulators from lymphocytes, and chem. transmitters from neurons. In animal cells, serine/threonine kinases including cAMP-dependent protein kinase, protein kinase C and calmodulin kinases have been implicated in calcium-signal transduction leading to regulated secretion. Although plants and protozoa also regulate secretion by means of intracellular calcium, the method by which these signals are relayed has not been explained. Here we show that the Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) is an essential regulator of calcium-dependent exocytosis in this opportunistic human pathogen. Conditional suppression of TgCDPK1 revealed that it controls calcium-dependent secretion of specialized organelles called micronemes, resulting in a block of essential phenotypes including parasite motility, host-cell invasion, and egress. These phenotypes were recapitulated by using a chem. biol. approach in which pyrazolopyrimidine-derived compds. specifically inhibited TgCDPK1 and disrupted the parasite's life cycle at stages dependent on microneme secretion. Inhibition was specific to TgCDPK1, because expression of a resistant mutant kinase reversed sensitivity to the inhibitor. TgCDPK1 is conserved among apicomplexans and belongs to a family of kinases shared with plants and ciliates, suggesting that related CDPKs may have a function in calcium-regulated secretion in other organisms. Because this kinase family is absent from mammalian hosts, it represents a validated target that may be exploitable for chemotherapy against T. gondii and related apicomplexans.
- 281Hui, R.; El Bakkouri, M.; Sibley, L. D. Designing selective inhibitors for calcium-dependent protein kinases in apicomplexans. Trends Pharmacol. Sci. 2015, 36, 452– 460, DOI: 10.1016/j.tips.2015.04.011[Crossref], [PubMed], [CAS], Google Scholar281https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXotVWitLk%253D&md5=0081edfce5d381c6a34c396b011c24b8Designing selective inhibitors for calcium-dependent protein kinases in apicomplexansHui, Raymond; El Bakkouri, Majida; Sibley, L. DavidTrends in Pharmacological Sciences (2015), 36 (7), 452-460CODEN: TPHSDY; ISSN:0165-6147. (Elsevier Ltd.)A review. Apicomplexan parasites cause some of the most severe human diseases, including malaria (caused by Plasmodium), toxoplasmosis, and cryptosporidiosis. Treatments are limited by the lack of effective drugs and development of resistance to available agents. By exploiting novel features of protein kinases in these parasites, it may be possible to develop new treatments. We summarize here recent advances in identifying small mol. inhibitors against a novel family of plant-like, calcium-dependent kinases that are uniquely expanded in apicomplexan parasites. Anal. of the 3D structure, activation mechanism, and sensitivity to small mols. had identified several attractive chem. scaffolds that are potent and selective inhibitors of these parasite kinases. Further optimization of these leads may yield promising new drugs for treatment of these parasitic infections.
- 282Johnson, S. M.; Murphy, R. C.; Geiger, J. A.; DeRocher, A. E.; Zhang, Z.; Ojo, K. K.; Larson, E. T.; Perera, B. G.; Dale, E. J.; He, P.; Reid, M. C.; Fox, A. M.; Mueller, N. R.; Merritt, E. A.; Fan, E.; Parsons, M.; Van Voorhis, W. C.; Maly, D. J. Development of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) inhibitors with potent anti-toxoplasma activity. J. Med. Chem. 2012, 55, 2416– 2426, DOI: 10.1021/jm201713h[ACS Full Text], [CAS], Google Scholar282https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XitVeksb8%253D&md5=862ac0e5066f60d7eeaccc723c2c4e75Development of Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitors with Potent Anti-Toxoplasma ActivityJohnson, Steven M.; Murphy, Ryan C.; Geiger, Jennifer A.; DeRocher, Amy E.; Zhang, Zhongsheng; Ojo, Kayode K.; Larson, Eric T.; Perera, B. Gayani K.; Dale, Edward J.; He, Panqing; Reid, Molly C.; Fox, Anna M. W.; Mueller, Natascha R.; Merritt, Ethan A.; Fan, Erkang; Parsons, Marilyn; Van Voorhis, Wesley C.; Maly, Dustin J.Journal of Medicinal Chemistry (2012), 55 (5), 2416-2426CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Toxoplasmosis is a disease of prominent health concern that is caused by the protozoan parasite Toxoplasma gondii. Proliferation of T. gondii is dependent on its ability to invade host cells, which is mediated in part by calcium-dependent protein kinase 1 (CDPK1). We have developed ATP competitive inhibitors of TgCDPK1 that block invasion of parasites into host cells, preventing their proliferation. The presence of a unique glycine gatekeeper residue in TgCDPK1 permits selective inhibition of the parasite enzyme over human kinases. These potent TgCDPK1 inhibitors do not inhibit the growth of human cell lines and represent promising candidates as toxoplasmosis therapeutics.
- 283Lourido, S.; Zhang, C.; Lopez, M. S.; Tang, K.; Barks, J.; Wang, Q.; Wildman, S. A.; Shokat, K. M.; Sibley, L. D. Optimizing small molecule inhibitors of calcium-dependent protein kinase 1 to prevent infection by Toxoplasma gondii. J. Med. Chem. 2013, 56, 3068– 3077, DOI: 10.1021/jm4001314[ACS Full Text], [CAS], Google Scholar283https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjslSgt78%253D&md5=352bb9e5b5304656aab52da763202b68Optimizing Small Molecule Inhibitors of Calcium-Dependent Protein Kinase 1 to Prevent Infection by Toxoplasma gondiiLourido, Sebastian; Zhang, Chao; Lopez, Michael S.; Tang, Keliang; Barks, Jennifer; Wang, Qiuling; Wildman, Scott A.; Shokat, Kevan M.; Sibley, L. DavidJournal of Medicinal Chemistry (2013), 56 (7), 3068-3077CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Toxoplasma gondii is sensitive to bulky pyrazolo [3,4-d] pyrimidine (PP) inhibitors due to the presence of a Gly gatekeeper in the essential calcium dependent protein kinase 1 (CDPK1). Here we synthesized a no. of new derivs. of 3-methyl-benzyl-PP (3-MB-PP, or 1). The potency of PP analogs in inhibiting CDPK1 enzyme activity in vitro (low nM IC50 values) and blocking parasite growth in host cell monolayers in vivo (low μM EC50 values) were highly correlated and occurred in a CDPK1-specific manner. Chem. modification of the PP scaffold to increase half-life in the presence of microsomes in vitro led to identification of compds. with enhanced stability while retaining activity. Several of these more potent compds. were able to prevent lethal infection with T. gondii in the mouse model. Collectively, the strategies outlined here provide a route for development of more effective compds. for treatment of toxoplasmosis and perhaps related parasitic diseases.
- 284Vidadala, R. S.; Rivas, K. L.; Ojo, K. K.; Hulverson, M. A.; Zambriski, J. A.; Bruzual, I.; Schultz, T. L.; Huang, W.; Zhang, Z.; Scheele, S.; DeRocher, A. E.; Choi, R.; Barrett, L. K.; Siddaramaiah, L. K.; Hol, W. G.; Fan, E.; Merritt, E. A.; Parsons, M.; Freiberg, G.; Marsh, K.; Kempf, D. J.; Carruthers, V. B.; Isoherranen, N.; Doggett, J. S.; Van Voorhis, W. C.; Maly, D. J. Development of an orally available and central nervous system (CNS) penetrant Toxoplasma gondii Calcium-dependent protein kinase 1 (TgCDPK1) inhibitor with minimal human ether-a-go-go-related gene (hERG) activity for the treatment of Toxoplasmosis. J. Med. Chem. 2016, 59, 6531– 6546, DOI: 10.1021/acs.jmedchem.6b00760[ACS Full Text], [CAS], Google Scholar284https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVSrsr%252FM&md5=8eb12f3703985ad69b921f1495858081Development of an Orally Available and Central Nervous System (CNS) Penetrant Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related Gene (hERG) Activity for the Treatment of ToxoplasmosisVidadala, Rama Subba Rao; Rivas, Kasey L.; Ojo, Kayode K.; Hulverson, Matthew A.; Zambriski, Jennifer A.; Bruzual, Igor; Schultz, Tracey L.; Huang, Wenlin; Zhang, Zhongsheng; Scheele, Suzanne; DeRocher, Amy E.; Choi, Ryan; Barrett, Lynn K.; Siddaramaiah, Latha Kallur; Hol, Wim G. J.; Fan, Erkang; Merritt, Ethan A.; Parsons, Marilyn; Freiberg, Gail; Marsh, Kennan; Kempf, Dale J.; Carruthers, Vern B.; Isoherranen, Nina; Doggett, J. Stone; Van Voorhis, Wesley C.; Maly, Dustin J.Journal of Medicinal Chemistry (2016), 59 (13), 6531-6546CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)New therapies are needed for the treatment of toxoplasmosis, which is a disease caused by the protozoan parasite Toxoplasma gondii. To this end, we previously developed a potent and selective inhibitor (compd. 1) of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) that possesses antitoxoplasmosis activity in vitro and in vivo. Unfortunately, 1 has potent human ether-a-go-go-related gene (hERG) inhibitory activity, assocd. with long Q-T syndrome, and consequently presents a cardiotoxicity risk. Here, we describe the identification of an optimized TgCDPK1 inhibitor 32, which does not have a hERG liability and possesses a favorable pharmacokinetic profile in small and large animals. 32(I) is CNS-penetrant and highly effective in acute and latent mouse models of T. gondii infection, significantly reducing the amt. of parasite in the brain, spleen, and peritoneal fluid and reducing brain cysts by >85%. These properties make 32 a promising lead for the development of a new antitoxoplasmosis therapy.
- 285Rutaganira, F. U.; Barks, J.; Dhason, M. S.; Wang, Q.; Lopez, M. S.; Long, S.; Radke, J. B.; Jones, N. G.; Maddirala, A. R.; Janetka, J. W.; El Bakkouri, M.; Hui, R.; Shokat, K. M.; Sibley, L. D. nhibition of Calcium dependent protein kinase 1 (CDPK1) by pyrazolopyrimidine analogs decreases establishment and reoccurrence of central nervous system disease by Toxoplasma gondii. J. Med. Chem. 2017, 60, 9976– 9989, DOI: 10.1021/acs.jmedchem.7b01192[ACS Full Text], [CAS], Google Scholar285https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFensbzO&md5=27908eedbcadb1132f254fda63336842Inhibition of Calcium Dependent Protein Kinase 1 (CDPK1) by Pyrazolopyrimidine Analogs Decreases Establishment and Reoccurrence of Central Nervous System Disease by Toxoplasma gondiiRutaganira, Florentine U.; Barks, Jennifer; Dhason, Mary Savari; Wang, Qiuling; Lopez, Michael S.; Long, Shaojun; Radke, Joshua B.; Jones, Nathaniel G.; Maddirala, Amarendar R.; Janetka, James W.; El Bakkouri, Majida; Hui, Raymond; Shokat, Kevan M.; Sibley, L. DavidJournal of Medicinal Chemistry (2017), 60 (24), 9976-9989CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Calcium dependent protein kinase 1 (CDPK1) is an essential enzyme in the opportunistic pathogen Toxoplasma gondii. CDPK1 controls multiple processes that are crit. to the intracellular replicative cycle of T. gondii including secretion of adhesins, motility, invasion, and egress. Remarkably, CDPK1 contains a small glycine gatekeeper residue in the ATP binding pocket making it sensitive to ATP-competitive inhibitors with bulky substituents that complement this expanded binding pocket. Here the authors explored structure-activity relationships of a series of pyrazolopyrimidine inhibitors of CDPK1 with the goal of increasing selectivity over host enzymes, improving antiparasite potency, and improving metabolic stability. The resulting lead compd. 24 exhibited excellent enzyme inhibition and selectivity for CDPK1 and potently inhibited parasite growth in vitro. Compd. 24 was also effective at treating acute toxoplasmosis in the mouse, reducing dissemination to the central nervous system, and decreasing reactivation of chronic infection in severely immunocompromised mice. These findings provide proof of concept for the development of small mol. inhibitors of CDPK1 for treatment of CNS toxoplasmosis.
- 286Janetka, J. W.; Hopper, A. T.; Yang, Z.; Barks, J.; Dhason, M. S.; Wang, Q.; Sibley, L. D. Optimizing pyrazolopyrimidine inhibitors of Calcium dependent protein kinase 1 for treatment of acute and chronic toxoplasmosis. J. Med. Chem. 2020, 63, 6144– 6163, DOI: 10.1021/acs.jmedchem.0c00419[ACS Full Text], [CAS], Google Scholar286https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXpsFelsL0%253D&md5=6faff1fe52c7b11a9c51298b73d86f6dOptimizing Pyrazolopyrimidine Inhibitors of Calcium Dependent Protein Kinase 1 for Treatment of Acute and Chronic ToxoplasmosisJanetka, James W.; Hopper, Allen T.; Yang, Ziping; Barks, Jennifer; Dhason, Mary Savari; Wang, Qiuling; Sibley, L. DavidJournal of Medicinal Chemistry (2020), 63 (11), 6144-6163CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Calcium dependent protein kinase 1 (CDPK1) is an essential Ser/Thr kinase that controls invasion and egress by the protozoan parasite Toxoplasma gondii. The Gly gatekeeper of CDPK1 makes it exquisitely sensitive to inhibition by small mol. 1H-Pyrazolo[3,4-d]Pyrimidine-4-amine or (PP) compds. that are bulky ATP mimetics. Here we rationally designed, synthesized, and tested a series of novel PP analogs that were evaluated for inhibition of CDPK1 enzyme activity in vitro and parasite growth in cell culture. Optimal substitution on the PP scaffold included 2-pyridyl ethers directed into the hydrophobic pocket and small carbocyclic rings accessing the ribose-binding pocket. Further optimization of the series led to identification of the lead compd. I that displayed excellent potency, selectivity, safety profile, and efficacy in vivo. The results of these studies provide a foundation for further work to optimize CDPK1 inhibitors for the treatment of acute and chronic toxoplasmosis.
- 287Chen, W. C.; Simanjuntak, Y.; Chu, L. W.; Ping, Y. H.; Lee, Y. L.; Lin, Y. L.; Li, W. S. Benzenesulfonamide derivatives as Calcium/calmodulin-dependent protein kinase inhibitors and antiviral agents against dengue and zika virus infections. J. Med. Chem. 2020, 63, 1313– 1327, DOI: 10.1021/acs.jmedchem.9b01779[ACS Full Text], [CAS], Google Scholar287https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhs1elsbg%253D&md5=4222b9a25616a59243c22bfd57b223e7Benzenesulfonamide Derivatives as Calcium/Calmodulin-Dependent Protein Kinase Inhibitors and Antiviral Agents against Dengue and Zika Virus InfectionsChen, Wei-Chia; Simanjuntak, Yogy; Chu, Li-Wei; Ping, Yueh-Hsin; Lee, Yi-Ling; Lin, Yi-Ling; Li, Wen-ShanJournal of Medicinal Chemistry (2020), 63 (3), 1313-1327CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Emerging and resurging mosquito-borne flaviviruses are an important public health challenge. The increased prevalence of dengue virus (DENV) infection has had a significant socioeconomic impact on epidemic countries. The recent outbreak of Zika virus (ZIKV) has created an international public health emergency because ZIKV infection has been linked to congenital defects and Guillain-Barr´e syndrome. To develop potentially prophylactic antiviral drugs for combating these acute infectious diseases, we have targeted the host calcium/calmodulin-dependent kinase II (CaMKII) for inhibition. By using CaMKII structure-guided inhibitor design, we generated four families of benzenesulfonamide (BSA) derivs. for SAR anal. Among these substances, N-(4-cycloheptyl-4-oxobutyl)-4-methoxy-N-phenylbenzenesulfonamide (9) showed superior properties as a lead CaMKII inhibitor and antiviral agent. BSA 9 inhibited CaMKII activity with an IC50 value of 0.79 μM and displayed EC50 values of 1.52 μM and 1.91 μM against DENV and ZIKV infections of human neuronal BE(2)C cells, resp. Notably, 9 significantly reduced the viremia level and increased animal survival time in mouse-challenge models.
- 288Verdonck, S.; Pu, S. Y.; Sorrell, F. J.; Elkins, J. M.; Froeyen, M.; Gao, L. J.; Prugar, L. I.; Dorosky, D. E.; Brannan, J. M.; Barouch-Bentov, R.; Knapp, S.; Dye, J. M.; Herdewijn, P.; Einav, S.; De Jonghe, S. Synthesis and structure-activity relationships of 3,5-disubstituted-pyrrolo[2,3- b]pyridines as inhibitors of Adaptor-associated kinase 1 with antiviral activity. J. Med. Chem. 2019, 62, 5810– 5831, DOI: 10.1021/acs.jmedchem.9b00136[ACS Full Text], [CAS], Google Scholar288https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtVKgtr7P&md5=bdec475534dbe2ad18d1c377f8b4c67dSynthesis and Structure-Activity Relationships of 3,5-Disubstituted-pyrrolo[2,3-b]pyridines as Inhibitors of Adaptor-Associated Kinase 1 with Antiviral ActivityVerdonck, Sven; Pu, Szu-Yuan; Sorrell, Fiona J.; Elkins, Jon M.; Froeyen, Mathy; Gao, Ling-Jie; Prugar, Laura I.; Dorosky, Danielle E.; Brannan, Jennifer M.; Barouch-Bentov, Rina; Knapp, Stefan; Dye, John M.; Herdewijn, Piet; Einav, Shirit; De Jonghe, StevenJournal of Medicinal Chemistry (2019), 62 (12), 5810-5831CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)There are currently no approved drugs for the treatment of emerging viral infections, such as dengue and Ebola. Adaptor-assocd. kinase 1 (AAK1) is a cellular serine-threonine protein kinase that functions as a key regulator of the clathrin-assocd. host adaptor proteins and regulates the intracellular trafficking of multiple unrelated RNA viruses. Moreover, AAK1 is overexpressed specifically in dengue virus-infected but not bystander cells. Because AAK1 is a promising antiviral drug target, we have embarked on an optimization campaign of a previously identified 7-azaindole analog, yielding novel pyrrolo[2,3-b]pyridines with high AAK1 affinity. The optimized compds. demonstrate improved activity against dengue virus both in vitro and in human primary dendritic cells and the unrelated Ebola virus. These findings demonstrate that targeting cellular AAK1 may represent a promising broad-spectrum antiviral strategy.
- 289Mohedas, A. H.; Wang, Y.; Sanvitale, C. E.; Canning, P.; Choi, S.; Xing, X.; Bullock, A. N.; Cuny, G. D.; Yu, P. B. Structure-activity relationship of 3,5-diaryl-2-aminopyridine ALK2 inhibitors reveals unaltered binding affinity for fibrodysplasia ossificans progressiva causing mutants. J. Med. Chem. 2014, 57, 7900– 7915, DOI: 10.1021/jm501177w[ACS Full Text], [CAS], Google Scholar289https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht12gu7fP&md5=c5efce9b3d06bbb126aa8a197d3d2b40Structure-Activity Relationship of 3,5-Diaryl-2-aminopyridine ALK2 Inhibitors Reveals Unaltered Binding Affinity for Fibrodysplasia Ossificans Progressiva Causing MutantsMohedas, Agustin H.; Wang, You; Sanvitale, Caroline E.; Canning, Peter; Choi, Sungwoon; Xing, Xuechao; Bullock, Alex N.; Cuny, Gregory D.; Yu, Paul B.Journal of Medicinal Chemistry (2014), 57 (19), 7900-7915CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)There are currently no effective therapies for fibrodysplasia ossificans progressiva (FOP), a debilitating and progressive heterotopic ossification disease caused by activating mutations of ACVR1 encoding the BMP type I receptor kinase ALK2. Recently, a subset of these same mutations of ACVR1 have been identified in diffuse intrinsic pontine glioma (DIPG) tumors. Here the authors describe the structure-activity relationship for a series of novel ALK2 inhibitors based on the 2-aminopyridine compd. K02288. Several modifications increased potency in kinase, thermal shift, or cell-based assays of BMP signaling and transcription, as well as selectivity for ALK2 vs. closely related BMP and TGF-β type I receptor kinases. Compds. in this series exhibited a wide range of in vitro cytotoxicity that was not correlated with potency or selectivity, suggesting mechanisms independent of BMP or TGF-β inhibition. The study also highlights a potent 2-methylpyridine deriv. I (LDN-214117) with a high degree of selectivity for ALK2 and low cytotoxicity that could provide a template for preclin. development. Contrary to the notion that activating mutations of ALK2 might alter inhibitor efficacy due to potential conformational changes in the ATP-binding site, the compds. demonstrated consistent binding to a panel of mutant and wild-type ALK2 proteins. Thus, BMP inhibitors identified via activity against wild-type ALK2 signaling are likely to be of clin. relevance for the diverse ALK2 mutant proteins assocd. with FOP and DIPG.
- 290Fushimi, M.; Fujimori, I.; Wakabayashi, T.; Hasui, T.; Kawakita, Y.; Imamura, K.; Kato, T.; Murakami, M.; Ishii, T.; Kikko, Y.; Kasahara, M.; Nakatani, A.; Hiura, Y.; Miyamoto, M.; Saikatendu, K.; Zou, H.; Lane, S. W.; Lawson, J. D.; Imoto, H. Discovery of potent, selective, and brain-penetrant 1 H-pyrazol-5-yl-1 H-pyrrolo[2,3- b]pyridines as Anaplastic lymphoma kinase (ALK) inhibitors. J. Med. Chem. 2019, 62, 4915– 4935, DOI: 10.1021/acs.jmedchem.8b01630[ACS Full Text], [CAS], Google Scholar290https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXnvFCgsrg%253D&md5=8d3bac7f718930a6102cb7855af501cbDiscovery of potent, selective, and brain-penetrant 1H-pyrazol-5-yl-1H-pyrrolo[2,3-b]pyridines as anaplastic lymphoma kinase (ALK) inhibitorsFushimi, Makoto; Fujimori, Ikuo; Wakabayashi, Takeshi; Hasui, Tomoaki; Kawakita, Youichi; Imamura, Keisuke; Kato, Tomoko; Murakami, Morio; Ishii, Tsuyoshi; Kikko, Yorifumi; Kasahara, Maki; Nakatani, Atsushi; Hiura, Yuto; Miyamoto, Maki; Saikatendu, Kumar; Zou, Hua; Lane, Scott Weston; Lawson, J. David; Imoto, HiroshiJournal of Medicinal Chemistry (2019), 62 (10), 4915-4935CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Anaplastic lymphoma kinase (ALK), a member of the receptor tyrosine kinase family, is predominantly expressed in the brain and implicated in neuronal development and cognition. However, the detailed function of ALK in the central nervous system (CNS) is still unclear. To elucidate the role of ALK in the CNS, it was necessary to discover a potent, selective, and brain-penetrant ALK inhibitor. Scaffold hopping and lead optimization of N-(2,4-difluorobenzyl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-amine 1 guided by a cocrystal structure of compd. 1 bound to ALK resulted in the identification of (6-(1-(5-fluoropyridin-2-yl)ethoxy)-1-(5-methyl-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)((2S)-2-methylmorpholin-4-yl)methanone 13 as a highly potent, selective, and brain-penetrable compd. I.p. administration of compd. 13 significantly decreased the phosphorylated-ALK (p-ALK) levels in the hippocampus and prefrontal cortex in the mouse brain. These results suggest that compd. 13 could serve as a useful chem. probe to elucidate the mechanism of ALK-mediated brain functions and the therapeutic potential of ALK inhibition.
- 291Bung, N.; Surepalli, S.; Seshadri, S.; Patel, S.; Peddasomayajula, S.; Kummari, L. K.; Kumar, S. T.; Babu, P. P.; Parsa, K. V. L.; Poondra, R. R.; Bulusu, G.; Misra, P. 2-[2-(4-(trifluoromethyl)phenylamino)thiazol-4-yl]acetic acid (Activator-3) is a potent activator of AMPK. Sci. Rep. 2018, 8, 9599, DOI: 10.1038/s41598-018-27974-1[Crossref], [PubMed], [CAS], Google Scholar291https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3c%252FhslChtA%253D%253D&md5=221665dc3822f9b7f7b40a1ed559524c2-[2-(4-(trifluoromethyl)phenylamino)thiazol-4-yl]acetic acid (Activator-3) is a potent activator of AMPKBung Navneet; Bulusu Gopalakrishnan; Surepalli Sobhitha; Peddasomayajula Saranya; Kummari Lalith Kumar; Parsa Kishore V L; Poondra Rajamohan Reddy; Bulusu Gopalakrishnan; Misra Parimal; Seshadri Sriram; Patel Sweta; Kummari Lalith Kumar; Kummari Lalith Kumar; Kumar Sireesh T; Babu Phanithi PrakashScientific reports (2018), 8 (1), 9599 ISSN:.AMPK is considered as a potential high value target for metabolic disorders. Here, we present the molecular modeling, in vitro and in vivo characterization of Activator-3, 2-[2-(4-(trifluoromethyl)phenylamino)thiazol-4-yl]acetic acid, an AMP mimetic and a potent pan-AMPK activator. Activator-3 and AMP likely share common activation mode for AMPK activation. Activator-3 enhanced AMPK phosphorylation by upstream kinase LKB1 and protected AMPK complex against dephosphorylation by PP2C. Molecular modeling analyses followed by in vitro mutant AMPK enzyme assays demonstrate that Activator-3 interacts with R70 and R152 of the CBS1 domain on AMPK γ subunit near AMP binding site. Activator-3 and C2, a recently described AMPK mimetic, bind differently in the γ subunit of AMPK. Activator-3 unlike C2 does not show cooperativity of AMPK activity in the presence of physiological concentration of ATP (2 mM). Activator-3 displays good pharmacokinetic profile in rat blood plasma with minimal brain penetration property. Oral treatment of High Sucrose Diet (HSD) fed diabetic rats with 10 mg/kg dose of Activator-3 once in a day for 30 days significantly enhanced glucose utilization, improved lipid profiles and reduced body weight, demonstrating that Activator-3 is a potent AMPK activator that can alleviate the negative metabolic impact of high sucrose diet in rat model.
- 292Lee, T. W.; Verhey, T. B.; Antiperovitch, P. A.; Atamanyuk, D.; Desroy, N.; Oliveira, C.; Denis, A.; Gerusz, V.; Drocourt, E.; Loutet, S. A.; Hamad, M. A.; Stanetty, C.; Andres, S. N.; Sugiman-Marangos, S.; Kosma, P.; Valvano, M. A.; Moreau, F.; Junop, M. S. Structural-functional studies of Burkholderia cenocepacia D-glycero-β-D-manno-heptose 7-phosphate kinase (HldA) and characterization of inhibitors with antibiotic adjuvant and antivirulence properties. J. Med. Chem. 2013, 56, 1405– 1417, DOI: 10.1021/jm301483h[ACS Full Text], [CAS], Google Scholar292https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVyiurrI&md5=288f3ec86757f6d49c86f8dad3927223Structural-Functional Studies of Burkholderia cenocepacia D-Glycero-β-D-manno-heptose 7-Phosphate Kinase (HldA) and Characterization of Inhibitors with Antibiotic Adjuvant and Antivirulence PropertiesLee, Ting-Wai; Verhey, Theodore B.; Antiperovitch, Pavel A.; Atamanyuk, Dmytro; Desroy, Nicolas; Oliveira, Chrystelle; Denis, Alexis; Gerusz, Vincent; Drocourt, Elodie; Loutet, Slade A.; Hamad, Mohamad A.; Stanetty, Christian; Andres, Sara N.; Sugiman-Marangos, Seiji; Kosma, Paul; Valvano, Miguel A.; Moreau, Francois; Junop, Murray S.Journal of Medicinal Chemistry (2013), 56 (4), 1405-1417CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)As an essential constituent of the outer membrane of Gram-neg. bacteria, lipopolysaccharide contributes significantly to virulence and antibiotic resistance. The lipopolysaccharide biosynthetic pathway therefore serves as a promising therapeutic target for antivirulence drugs and antibiotic adjuvants. Here we report the structural-functional studies of D-glycero-β-D-manno-heptose 7-phosphate kinase (HldA), an absolutely conserved enzyme in this pathway, from Burkholderia cenocepacia. HldA is structurally similar to members of the PfkB carbohydrate kinase family and appears to catalyze heptose phosphorylation via an in-line mechanism mediated mainly by a conserved aspartate, Asp270. Moreover, we report the structures of HldA in complex with two potent inhibitors in which both inhibitors adopt a folded conformation and occupy the nucleotide-binding sites. Together, these results provide important insight into the mechanism of HldA-catalyzed heptose phosphorylation and necessary information for further development of HldA inhibitors.
- 293Mente, S.; Arnold, E.; Butler, T.; Chakrapani, S.; Chandrasekaran, R.; Cherry, K.; DiRico, K.; Doran, A.; Fisher, K.; Galatsis, P.; Green, M.; Hayward, M.; Humphrey, J.; Knafels, J.; Li, J.; Liu, S.; Marconi, M.; McDonald, S.; Ohren, J.; Paradis, V.; Sneed, B.; Walton, K.; Wager, T. Ligand-protein interactions of selective casein kinase 1δ inhibitors. J. Med. Chem. 2013, 56, 6819– 6828, DOI: 10.1021/jm4006324[ACS Full Text], [CAS], Google Scholar293https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1Wlt7jE&md5=bdc600c0977cc4f0f4de40882e1c17b5Ligand-Protein Interactions of Selective Casein Kinase 1δ InhibitorsMente, Scot; Arnold, Eric; Butler, Todd; Chakrapani, Subramanyam; Chandrasekaran, Ramalakshmi; Cherry, Kevin; DiRico, Ken; Doran, Angela; Fisher, Katherine; Galatsis, Paul; Green, Michael; Hayward, Matthew; Humphrey, John; Knafels, John; Li, Jianke; Liu, Shenping; Marconi, Michael; McDonald, Scott; Ohren, Jeff; Paradis, Vanessa; Sneed, Blossom; Walton, Kevin; Wager, TravisJournal of Medicinal Chemistry (2013), 56 (17), 6819-6828CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Casein kinase 1δ (CK1δ) and 1ε (CK1ε) are believed to be necessary enzymes for the regulation of circadian rhythms in all mammals. On the basis of the authors' previously published work demonstrating a CK1ε-preferring compd. to be an ineffective circadian clock modulator, the authors have synthesized a series of pyrazole-substituted pyridine inhibitors, selective for the CK1δ isoform. Addnl., using structure-based drug design, the authors have been able to exploit differences in the hinge region between CK1δ and p38 to find selective inhibitors that have minimal p38 activity. The SAR, brain exposure, and the effect of these inhibitors on mouse circadian rhythms are described. The in vivo evaluation of these inhibitors demonstrates that selective inhibition of CK1δ at sufficient central exposure levels is capable of modulating circadian rhythms.
- 294Lee, J. W.; Hirota, T.; Ono, D.; Honma, S.; Honma, K. I.; Park, K.; Kay, S. A. Chemical control of mammalian circadian behavior through dual inhibition of Casein kinase iα and δ. J. Med. Chem. 2019, 62, 1989– 1998, DOI: 10.1021/acs.jmedchem.8b01541[ACS Full Text], [CAS], Google Scholar294https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisVWjsr0%253D&md5=e7348872080ba7a8f8dc7c25c82b640eChemical control of mammalian circadian behavior through dual inhibition of casein kinase Iα and δLee, Jae Wook; Hirota, Tsuyoshi; Ono, Daisuke; Honma, Sato; Honma, Ken-ichi; Park, Keunwan; Kay, Steve A.Journal of Medicinal Chemistry (2019), 62 (4), 1989-1998CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Circadian rhythms are controlled by transcriptional feedback loops of clock genes and proteins. The stability of clock proteins is regulated by post-translational modification, such as phosphorylation by kinases. In particular, casein kinase I (CKI) phosphorylates the PER protein to regulate proteasomal degrdn. and nuclear localization. Therefore, CKI inhibition can modulate mammalian circadian rhythms. In the present study, we have developed novel CKIα and CKIδ dual inhibitors by extensive structural modification of N9 and C2 position of longdaysin. We identified NCC007 (I) that showed stronger period effects (0.32 μM for 5 h period lengthening) in a cell-based circadian assay. The following in vitro kinase assay showed that I inhibited CKIα and CKIδ with an IC50 of 1.8 and 3.6 μM. We further demonstrated that I lengthened the period of mouse behavioral rhythms in vivo. Thus, I is a valuable tool compd. to control circadian rhythms through CKI inhibition.
- 295Salado, I. G.; Redondo, M.; Bello, M. L.; Perez, C.; Liachko, N. F.; Kraemer, B. C.; Miguel, L.; Lecourtois, M.; Gil, C.; Martinez, A.; Perez, D. I. Protein kinase CK-1 inhibitors as new potential drugs for amyotrophic lateral sclerosis. J. Med. Chem. 2014, 57, 2755– 2772, DOI: 10.1021/jm500065f[ACS Full Text], [CAS], Google Scholar295https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXjsVehsLc%253D&md5=52aad257a2054c93a8fcbafab7a8cb3dProtein Kinase CK-1 Inhibitors As New Potential Drugs for Amyotrophic Lateral SclerosisSalado, Irene G.; Redondo, Miriam; Bello, Murilo L.; Perez, Concepcion; Liachko, Nicole F.; Kraemer, Brian C.; Miguel, Laetitia; Lecourtois, Magalie; Gil, Carmen; Martinez, Ana; Perez, Daniel I.Journal of Medicinal Chemistry (2014), 57 (6), 2755-2772CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease where motor neurons in cortex, brain stem, and spinal cord die progressively, resulting in muscle wasting, paralysis, and death. Currently, effective therapies for ALS are lacking; however, identification of pathol. TAR DNA-binding protein 43 (TDP-43) as the hallmark lesion in sporadic ALS suggests new therapeutic targets for pharmacol. intervention. Pathol. TDP-43 phosphorylation appears to drive the onset and progression of ALS and may result from upregulation of the protein kinase CK-1 in affected neurons, resulting in postranslational TDP-43 modification. Consequently, brain penetrant specific CK-1 inhibitors may provide a new therapeutic strategy for treating ALS and other TDP-43 proteinopathies. Using a chem. genetic approach, we report the discovery and further optimization of a no. of potent CK-1δ inhibitors. Moreover, these small heterocyclic mols. are able to prevent TDP-43 phosphorylation in cell cultures, to increase Drosophila lifespan by redn. of TDP-43 neurotoxicity, and are predicted to cross the blood-brain barrier. Thus, N-(benzothiazolyl)-2-phenyl-acetamides are valuable drug candidates for further studies and may be a new therapeutic approach for ALS and others pathologies in which TDP-43 is involved.
- 296Kovackova, S.; Chang, L.; Bekerman, E.; Neveu, G.; Barouch-Bentov, R.; Chaikuad, A.; Heroven, C.; Sala, M.; De Jonghe, S.; Knapp, S.; Einav, S.; Herdewijn, P. Selective inhibitors of cyclin G associated kinase (GAK) as anti-hepatitis C agents. J. Med. Chem. 2015, 58, 3393– 3410, DOI: 10.1021/jm501759m[ACS Full Text], [CAS], Google Scholar296https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXlsFGntLY%253D&md5=ed7f93eb3d49f6c7265dd2c0da880b43Selective Inhibitors of Cyclin G Associated Kinase (GAK) as Anti-Hepatitis C AgentsKovackova, Sona; Chang, Lei; Bekerman, Elena; Neveu, Gregory; Barouch-Bentov, Rina; Chaikuad, Apirat; Heroven, Christina; Sala, Michal; De Jonghe, Steven; Knapp, Stefan; Einav, Shirit; Herdewijn, PietJournal of Medicinal Chemistry (2015), 58 (8), 3393-3410CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Cyclin G assocd. kinase (GAK) emerged as a promising drug target for the treatment of viral infections. However, no potent and selective GAK inhibitors have been reported in the literature to date. This paper describes the discovery of isothiazolo[5,4-b]pyridines as selective GAK inhibitors, with the most potent congeners displaying low nanomolar binding affinity for GAK. Cocrystn. expts. revealed that these compds. behaved as classic type I ATP-competitive kinase inhibitors. In addn., the authors have demonstrated that these compds. exhibit a potent activity against hepatitis C virus (HCV) by inhibiting two temporally distinct steps in the HCV life cycle (i.e., viral entry and assembly). Hence, these GAK inhibitors represent chem. probes to study GAK function in different disease areas where GAK has been implicated (including viral infection, cancer, and Parkinson's disease).
- 297Pu, S. Y.; Wouters, R.; Schor, S.; Rozenski, J.; Barouch-Bentov, R.; Prugar, L. I.; O’Brien, C. M.; Brannan, J. M.; Dye, J. M.; Herdewijn, P.; De Jonghe, S.; Einav, S. Optimization of isothiazolo[4,3- b]pyridine-based inhibitors of cyclin G associated kinase (GAK) with broad-spectrum antiviral activity. J. Med. Chem. 2018, 61, 6178– 6192, DOI: 10.1021/acs.jmedchem.8b00613[ACS Full Text], [CAS], Google Scholar297https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXht1altLfP&md5=fe33e256835ea01c5e1932c3ccea7eacOptimization of Isothiazolo[4,3-b]pyridine-Based Inhibitors of Cyclin G Associated Kinase (GAK) with Broad-Spectrum Antiviral ActivityPu, Szu-Yuan; Wouters, Randy; Schor, Stanford; Rozenski, Jef; Barouch-Bentov, Rina; Prugar, Laura I.; O'Brien, Cecilia M.; Brannan, Jennifer M.; Dye, John M.; Herdewijn, Piet; De Jonghe, Steven; Einav, ShiritJournal of Medicinal Chemistry (2018), 61 (14), 6178-6192CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)There is an urgent need for strategies to combat dengue and other emerging viral infections. We reported that cyclin G-assocd. kinase (GAK), a cellular regulator of the clathrin-assocd. host adaptor proteins AP-1 and AP-2, regulates intracellular trafficking of multiple unrelated RNA viruses during early and late stages of the viral lifecycle. We also reported the discovery of potent, selective GAK inhibitors based on an isothiazolo[4,3-b]pyridine scaffold, albeit with moderate antiviral activity. Here, we describe our efforts leading to the discovery of novel isothiazolo[4,3-b]pyridines that maintain high GAK affinity and selectivity. These compds. demonstrate improved in vitro activity against dengue virus, including in human primary dendritic cells, and efficacy against the unrelated Ebola and chikungunya viruses. Moreover, inhibition of GAK activity was validated as an important mechanism of antiviral action of these compds. These findings demonstrate the potential utility of a GAK-targeted broad-spectrum approach for combating currently untreatable emerging viral infections.
- 298Glatthar, R.; Stojanovic, A.; Troxler, T.; Mattes, H.; Mobitz, H.; Beerli, R.; Blanz, J.; Gassmann, E.; Druckes, P.; Fendrich, G.; Gutmann, S.; Martiny-Baron, G.; Spence, F.; Hornfeld, J.; Peel, J. E.; Sparrer, H. Discovery of imidazoquinolines as a novel class of potent, selective, and in vivo efficacious cancer osaka thyroid (COT) kinase inhibitors. J. Med. Chem. 2016, 59, 7544– 7560, DOI: 10.1021/acs.jmedchem.6b00598[ACS Full Text], [CAS], Google Scholar298https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlSms7nN&md5=26f882f203e21bf78d9c9e5090f8fc5bDiscovery of Imidazoquinolines as a Novel Class of Potent, Selective, and in Vivo Efficacious Cancer Osaka Thyroid (COT) Kinase InhibitorsGlatthar, Ralf; Stojanovic, Aleksandar; Troxler, Thomas; Mattes, Henri; Mobitz, Henrik; Beerli, Rene; Blanz, Joachim; Gassmann, Ernst; Druckes, Peter; Fendrich, Gabriele; Gutmann, Sascha; Martiny-Baron, Georg; Spence, Fiona; Hornfeld, Jeff; Peel, John Edmonson; Sparrer, HelmutJournal of Medicinal Chemistry (2016), 59 (16), 7544-7560CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Cancer Osaka thyroid (COT) kinase is an important regulator of pro-inflammatory cytokines in macrophages. Thus, pharmacol. inhibition of COT should be a valid approach to therapeutically intervene in the pathogenesis of macrophage-driven inflammatory diseases such as rheumatoid arthritis. We report the discovery and chem. optimization of a novel series of COT kinase inhibitors, with unprecedented nanomolar potency for the inhibition of TNFα. Pharmacol. profiling in vivo revealed a high metab. of these compds. in rats which was demonstrated to be predominantly attributed to aldehyde oxidase. Due to the very low activity of hepatic AO in the dog, the selected candidate 32 displayed significant blood exposure in dogs which resulted in a clear prevention of inflammation-driven lameness. Taken together, the described compds. both potently and selectively inhibit COT kinase in primary human cells and ameliorate inflammatory pathologies in vivo, supporting the notion that COT is an appropriate therapeutic target for inflammatory diseases.
- 299Sun, Q. Z.; Lin, G. F.; Li, L. L.; Jin, X. T.; Huang, L. Y.; Zhang, G.; Yang, W.; Chen, K.; Xiang, R.; Chen, C.; Wei, Y. Q.; Lu, G. W.; Yang, S. Y. Discovery of potent and selective inhibitors of cdc2-like kinase 1 (CLK1) as a new class of autophagy inducers. J. Med. Chem. 2017, 60, 6337– 6352, DOI: 10.1021/acs.jmedchem.7b00665[ACS Full Text], [CAS], Google Scholar299https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFCmtLnE&md5=61f94754810e761bfbc2bd1fe19a1123Discovery of Potent and Selective Inhibitors of Cdc2-Like Kinase 1 (CLK1) as a New Class of Autophagy InducersSun, Qi-Zheng; Lin, Gui-Feng; Li, Lin-Li; Jin, Xi-Ting; Huang, Lu-Yi; Zhang, Guo; Yang, Wei; Chen, Kai; Xiang, Rong; Chen, Chong; Wei, Yu-Quan; Lu, Guang-Wen; Yang, Sheng-YongJournal of Medicinal Chemistry (2017), 60 (14), 6337-6352CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Autophagy inducers represent new promising agents for the treatment of a wide range of medical illnesses. However, safe autophagy inducers for clin. applications are lacking. Inhibition of cdc2-like kinase 1 (CLK1) was recently found to efficiently induce autophagy. Unfortunately, most of the known CLK1 inhibitors have unsatisfactory selectivity. Herein, we report the discovery of a series of new CLK1 inhibitors contg. the 1H-[1,2,3]triazolo[4,5-c]quinoline scaffold. Among them, compd. 25 was the most potent and selective, with an IC50 value of 2 nM against CLK1. The crystal structure of CLK1 complexed with compd. 25 was solved, and the potency and kinase selectivity of compd. 25 were interpreted. Compd. 25 was able to induce autophagy in in vitro assays and displayed significant hepatoprotective effects in the acetaminophen (APAP)-induced liver injury mouse model. Collectively, due to its potency and selectivity, compd. 25 could be used as a chem. probe or agent in future mechanism-of-action or autophagy-related disease therapy studies.
- 300Liachko, N. F.; McMillan, P. J.; Guthrie, C. R.; Bird, T. D.; Leverenz, J. B.; Kraemer, B. C. CDC7 inhibition blocks pathological TDP-43 phosphorylation and neurodegeneration. Ann. Neurol. 2013, 74, 39– 52, DOI: 10.1002/ana.23870[Crossref], [PubMed], [CAS], Google Scholar300https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtlKku7jF&md5=ef5b9758b78283441f7a7de22c8959b0CDC7 inhibition blocks pathological TDP-43 phosphorylation and neurodegenerationLiachko, Nicole F.; McMillan, Pamela J.; Guthrie, Chris R.; Bird, Thomas D.; Leverenz, James B.; Kraemer, Brian C.Annals of Neurology (2013), 74 (1), 39-52CODEN: ANNED3; ISSN:0364-5134. (Wiley-Liss, Inc.)Objective : Kinase hyperactivity occurs in both neurodegenerative disease and cancer. Lesions contg. hyperphosphorylated aggregated TDP-43 characterize amyotrophic lateral sclerosis and frontotemporal lobar degeneration with TDP-43 inclusions. Dual phosphorylation of TDP-43 at serines 409/410 (S409/410) drives neurotoxicity in disease models; therefore, TDP-43-specific kinases are candidate targets for intervention. Methods : To find therapeutic targets for the prevention of TDP-43 phosphorylation, we assembled and screened a comprehensive RNA interference library targeting kinases in TDP-43 transgenic Caenorhabditis elegans. Results : We show CDC7 robustly phosphorylates TDP-43 at pathol. residues S409/410 in C. elegans, in vitro, and in human cell culture. In frontotemporal lobar degeneration (FTLD)-TDP cases, CDC7 immunostaining overlaps with the phospho-TDP-43 pathol. found in frontal cortex. Furthermore, PHA767491, a small mol. inhibitor of CDC7, reduces TDP-43 phosphorylation and prevents TDP-43-dependent neurodegeneration in TDP-43-transgenic animals. Interpretation : Taken together, these data support CDC7 as a novel therapeutic target for TDP-43 proteinopathies, including FTLD-TDP and amyotrophic lateral sclerosis.
- 301Hazlitt, R. A.; Teitz, T.; Bonga, J. D.; Fang, J.; Diao, S.; Iconaru, L.; Yang, L.; Goktug, A. N.; Currier, D. G.; Chen, T.; Rankovic, Z.; Min, J.; Zuo, J. Development of second-generation CDK2 inhibitors for the prevention of cisplatin-induced hearing loss. J. Med. Chem. 2018, 61, 7700– 7709, DOI: 10.1021/acs.jmedchem.8b00669[ACS Full Text], [CAS], Google Scholar301https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsVOjsLvN&md5=ad407a81d1ee43b04f511f6fba8678d1Development of Second-Generation CDK2 Inhibitors for the Prevention of Cisplatin-Induced Hearing LossHazlitt, Robert A.; Teitz, Tal; Bonga, Justine D.; Fang, Jie; Diao, Shiyong; Iconaru, Luigi; Yang, Lei; Goktug, Asli N.; Currier, Duane G.; Chen, Taosheng; Rankovic, Zoran; Min, Jaeki; Zuo, JianJournal of Medicinal Chemistry (2018), 61 (17), 7700-7709CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)There are currently no FDA-approved therapies to prevent the hearing loss assocd. with the usage of cisplatin in chemotherapeutic regimens. We recently demonstrated that the pharmacol. inhibition with kenpaullone or genetic deletion of CDK2 preserved hearing function in animal models treated with cisplatin, which suggests that CDK2 is a promising therapeutic target to prevent cisplatin-induced ototoxicity. In this study, we identified two lead compds., AT7519 and AZD5438, from a focused library screen of 187 CDK2 inhibitors, performed in an immortalized cell line derived from neonatal mouse cochleae treated with cisplatin. Moreover, we screened 36 analogs of AT7519 and identified analog I, which exhibited an improved therapeutic index. When delivered locally, analog I and AZD5438 both provided significant protection against cisplatin-induced ototoxicity in mice. Thus, we have identified two addnl. compds. that prevent cisplatin-induced ototoxicity in vivo and provided further evidence that CDK2 is a druggable target for treating cisplatin-induced ototoxicity.
- 302Yang, L.; Gu, X.; Zhang, W.; Zhang, J.; Ma, Z. Cdk5 inhibitor roscovitine alleviates neuropathic pain in the dorsal root ganglia by downregulating N-methyl-D-aspartate receptor subunit 2A. Neurol Sci. 2014, 35, 1365– 1371, DOI: 10.1007/s10072-014-1713-9[Crossref], [PubMed], [CAS], Google Scholar302https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2crmsVagsg%253D%253D&md5=79f8b63373b76a67b6ba9deb8188a90eCdk5 inhibitor roscovitine alleviates neuropathic pain in the dorsal root ganglia by downregulating N-methyl-D-aspartate receptor subunit 2AYang Lei; Gu Xiaoping; Zhang Wei; Zhang Juan; Ma ZhengliangNeurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology (2014), 35 (9), 1365-71 ISSN:.Cyclin-dependent kinase 5 (Cdk5) is a member of the small proline-directed serine/threonine kinase family. Cdk5 is not involved in cell cycle regulation, but is implicated in neurodegenerative disorders. However, the role of Cdk5 in neuropathic pain remains unclear. This study aimed to evaluate the possibility that Cdk5 is involved in neuropathic pain in the dorsal root ganglia (DRG). We injected intrathecally Cdk5 inhibitor roscovitine in rat model of chronic compression of dorsal root ganglion and examined pain behaviors and the expression of N-methyl-d-aspartate receptor subunit 2A (NR2A) but not NR2B or NR1 in DRG. We found that roscovitine alleviated neuropathic pain, causing decline in paw withdrawal mechanical threshold and paw withdrawal thermal latency. Furthermore, roscovitine inhibited NR2A expression in DRG. These data suggest that Cdk5-NR2A pathway regulates neuropathic pain in DRG, and intrathecal injection of roscovitine could alleviate neuropathic pain. Our findings provide new insight into the analgesic effects of Roscovitine and identify Cdk5-NR2A pathway as a potential target for effective treatment of neuropathic pain.
- 303Fromont, C.; Atzori, A.; Kaur, D.; Hashmi, L.; Greco, G.; Cabanillas, A.; Nguyen, H. V.; Jones, D. H.; Garzon, M.; Varela, A.; Stevenson, B.; Iacobini, G. P.; Lenoir, M.; Rajesh, S.; Box, C.; Kumar, J.; Grant, P.; Novitskaya, V.; Morgan, J.; Sorrell, F. J.; Redondo, C.; Kramer, A.; Harris, C. J.; Leighton, B.; Vickers, S. P.; Cheetham, S. C.; Kenyon, C.; Grabowska, A. M.; Overduin, M.; Berditchevski, F.; Weston, C. J.; Knapp, S.; Fischer, P. M.; Butterworth, S. Discovery of highly selective inhibitors of Calmodulin-dependent kinases that restore insulin sensitivity in the diet-induced obesity in vivo mouse model. J. Med. Chem. 2020, 63, 6784– 6801, DOI: 10.1021/acs.jmedchem.9b01803[ACS Full Text], [CAS], Google Scholar303https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXpvFWqsLk%253D&md5=8eb74ed13110e8e35c04b85d84fca35cDiscovery of Highly Selective Inhibitors of Calmodulin-Dependent Kinases That Restore Insulin Sensitivity in the Diet-Induced Obesity in Vivo Mouse ModelFromont, Christophe; Atzori, Alessio; Kaur, Divneet; Hashmi, Lubna; Greco, Graziella; Cabanillas, Alejandro; Nguyen, Huy Van; Jones, D. Heulyn; Garzon, Miguel; Varela, Ana; Stevenson, Brett; Iacobini, Greg P.; Lenoir, Marc; Rajesh, Sundaresan; Box, Clare; Kumar, Jitendra; Grant, Paige; Novitskaya, Vera; Morgan, Juliet; Sorrell, Fiona J.; Redondo, Clara; Kramer, Andreas; Harris, C. John; Leighton, Brendan; Vickers, Steven P.; Cheetham, Sharon C.; Kenyon, Colin; Grabowska, Anna M.; Overduin, Michael; Berditchevski, Fedor; Weston, Chris J.; Knapp, Stefan; Fischer, Peter M.; Butterworth, SamJournal of Medicinal Chemistry (2020), 63 (13), 6784-6801CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Polymorphisms in the region of the calmodulin-dependent kinase isoform D (CaMK1D) gene are assocd. with increased incidence of diabetes, with the most common polymorphism resulting in increased recognition by transcription factors and increased protein expression. While reducing CaMK1D expression has a potentially beneficial effect on glucose processing in human hepatocytes, there are no known selective inhibitors of CaMK1 kinases that can be used to validate or translate these findings. Here we describe the development of a series of potent, selective, and drug-like CaMK1 inhibitors that are able to provide significant free target cover in mouse models and are therefore useful as in vivo tool compds. Our results show that a lead compd. from this series improves insulin sensitivity and glucose control in the diet-induced obesity mouse model after both acute and chronic administration, providing the first in vivo validation of CaMK1D as a target for diabetes therapeutics.
- 304Xie, Z.; Wu, B.; Liu, Y.; Ren, W.; Tong, L.; Xiang, C.; Wei, A.; Gao, Y.; Zeng, L.; Xie, H.; Tang, W.; Hu, Y. Novel class of Colony-stimulating factor 1 receptor kinase inhibitors based on an o-aminopyridyl alkynyl scaffold as potential treatment for inflammatory disorders. J. Med. Chem. 2020, 63, 1397– 1414, DOI: 10.1021/acs.jmedchem.9b01912[ACS Full Text], [CAS], Google Scholar304https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXnsl2guw%253D%253D&md5=8e35b5e75e5a657d6714156a708806a2Novel Class of Colony-Stimulating Factor 1 Receptor Kinase Inhibitors Based on an o-Aminopyridyl Alkynyl Scaffold as Potential Treatment for Inflammatory DisordersXie, Zhicheng; Wu, Bing; Liu, Yingqiang; Ren, Wenming; Tong, Linjiang; Xiang, Caigui; Wei, Aihuan; Gao, Yuanzhuo; Zeng, Limin; Xie, Hua; Tang, Wei; Hu, YouhongJournal of Medicinal Chemistry (2020), 63 (3), 1397-1414CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Colony-stimulating factor 1 receptor (CSF-1R) is involved in inflammatory disorders as well as in many types of cancer. Based on high-throughput screening and docking results, we performed a detailed structure-activity-relationship study, leading to the discovery of a new series of compds. with nanomolar IC50 values against CSF-1R without the inhibition of fibroblast growth factor receptors. One of the most promising hits, compd. 29, potently inhibited CSF-1R kinase with an IC50 value of 0.7 nM, while it showed no inhibition to the same family member FMS-like tyrosine kinase 3. Compd. 29 displayed excellent anti-inflammatory effects against RAW264.7 macrophages indicated by significant inhibition against the activation of the CSF-1R pathway with low cytotoxicity. In addn., compd. 29 exhibited strong in vivo anti-inflammatory efficacy alongside favorable drug characteristics. This novel compd. 29 may serve as a new drug candidate with promising applications in inflammatory disorders.
- 305El-Gamal, M. I.; Al-Ameen, S. K.; Al-Koumi, D. M.; Hamad, M. G.; Jalal, N. A.; Oh, C. H. Recent advances of colony-stimulating factor-1 receptor (CSF-1R) kinase and its inhibitors. J. Med. Chem. 2018, 61, 5450– 5466, DOI: 10.1021/acs.jmedchem.7b00873[ACS Full Text], [CAS], Google Scholar305https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvVWgtg%253D%253D&md5=9fa615ecf2f532f1a2f1bac1e4c48932Recent Advances of Colony-Stimulating Factor-1 Receptor (CSF-1R) Kinase and Its InhibitorsEl-Gamal, Mohammed I.; Al-Ameen, Shahad K.; Al-Koumi, Dania M.; Hamad, Mawadda G.; Jalal, Nouran A.; Oh, Chang-HyunJournal of Medicinal Chemistry (2018), 61 (13), 5450-5466CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Colony stimulation factor-1 receptor (CSF-1R), which is also known as FMS kinase, plays an important role in initiating inflammatory, cancer, and bone disorders when it is over-stimulated by its ligand, CSF-1. Innate immunity, as well as macrophage differentiation and survival, are regulated by the stimulation of the CSF-1R. Another ligand, interleukin-34 (IL-34), was recently reported to activate the CSF-1R receptor in a different manner. The relationship between CSF-1R and microglia has been reviewed. Both CSF-1 antibodies and small mol. CSF-1R kinase inhibitors have now been tested in animal models and in humans. In this Perspective, the authors discuss the role of CSF-1 and IL-34 in producing cancer, bone disorders, and inflammation. The authors also review the newly discovered and improved small mol. kinase inhibitors and monoclonal antibodies that have shown potent activity toward CSF-1R, reported from 2012 until 2017.
- 306Czarna, A.; Wang, J.; Zelencova, D.; Liu, Y.; Deng, X.; Choi, H. G.; Zhang, T.; Zhou, W.; Chang, J. W.; Kildalsen, H.; Seternes, O. M.; Gray, N. S.; Engh, R. A.; Rothweiler, U. Novel scaffolds for dual specificity tyrosine-phosphorylation-regulated kinase (DYRK1A) inhibitors. J. Med. Chem. 2018, 61, 7560– 7572, DOI: 10.1021/acs.jmedchem.7b01847[ACS Full Text], [CAS], Google Scholar306https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsVygtrjF&md5=c4b55fc7510b9f9d80726933b32be508Novel Scaffolds for Dual Specificity Tyrosine-Phosphorylation-Regulated Kinase (DYRK1A) InhibitorsCzarna, Anna; Wang, Jinhua; Zelencova, Diana; Liu, Yao; Deng, Xianming; Choi, Hwan Geun; Zhang, Tinghu; Zhou, Wenjun; Chang, Jae Won; Kildalsen, Hanne; Seternes, Ole Morten; Gray, Nathanael S.; Engh, Richard A.; Rothweiler, UlliJournal of Medicinal Chemistry (2018), 61 (17), 7560-7572CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)DYRK1A is one of five members of the dual-specificity tyrosine (Y) phosphorylation-regulated kinase (DYRK) family. The DYRK1A gene is located in the Down syndrome crit. region and regulates cellular processes related to proliferation and differentiation of neuronal progenitor cells during early development. This has focused research on its role in neuronal degenerative diseases, including Alzheimer's and Down syndrome. Recent studies have also shown a possible role of DYRK1A in diabetes. Here we report a variety of scaffolds not generally known for DYRK1A inhibition, demonstrating their effects in in vitro assays and also in cell cultures. These inhibitors effectively block the tau phosphorylation that is a hallmark of Alzheimer's disease. The crystal structures of these inhibitors support the design of optimized and novel therapeutics.
- 307Kumar, K.; Wang, P.; Wilson, J.; Zlatanic, V.; Berrouet, C.; Khamrui, S.; Secor, C.; Swartz, E. A.; Lazarus, M.; Sanchez, R.; Stewart, A. F.; Garcia-Ocana, A.; DeVita, R. J. Synthesis and biological validation of a harmine-based, central nervous system (CNS)-avoidant, selective, human β-cell regenerative Dual-specificity tyrosine phosphorylation-regulated kinase A (DYRK1A) inhibitor. J. Med. Chem. 2020, 63, 2986– 3003, DOI: 10.1021/acs.jmedchem.9b01379[ACS Full Text], [CAS], Google Scholar307https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitVOgsr8%253D&md5=c739edc1358acafc412a122c272edcebSynthesis and Biological Validation of a Harmine-Based, Central Nervous System (CNS)-Avoidant, Selective, Human β-Cell Regenerative Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase A (DYRK1A) InhibitorKumar, Kunal; Wang, Peng; Wilson, Jessica; Zlatanic, Viktor; Berrouet, Cecilia; Khamrui, Susmita; Secor, Cody; Swartz, Ethan A.; Lazarus, Michael; Sanchez, Roberto; Stewart, Andrew F.; Garcia-Ocana, Adolfo; DeVita, Robert J.Journal of Medicinal Chemistry (2020), 63 (6), 2986-3003CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Recently, our group identified that harmine is able to induce β-cell proliferation both in vitro and in vivo, mediated via the DYRK1A-NFAT pathway. Since, harmine suffers from a lack of selectivity, both against other kinases and CNS off-targets, we therefore sought to expand structure-activity relationships for harmine's DYRK1A activity, to enhance selectivity for off-targets while retaining human β-cell proliferation activity. We carried out optimization of the 9-N-position of harmine to synthesize 29 harmine-based analogs. Several novel inhibitors showed excellent DYRK1A inhibition and human β-cell proliferation capability. An optimized DYRK1A inhibitor, compd. I, was identified as a novel, efficacious in vivo lead candidate. Compd. I also demonstrates improved selectivity for kinases and CNS off-targets, as well as in vivo efficacy for β-cell proliferation and regeneration at lower doses than harmine. Collectively, these findings demonstrate that compd. I is a much improved in vivo lead candidate as compared to harmine for the treatment of diabetes.
- 308Liu, Y. A.; Jin, Q.; Zou, Y.; Ding, Q.; Yan, S.; Wang, Z.; Hao, X.; Nguyen, B.; Zhang, X.; Pan, J.; Mo, T.; Jacobsen, K.; Lam, T.; Wu, T. Y.; Petrassi, H. M.; Bursulaya, B.; DiDonato, M.; Gordon, W. P.; Liu, B.; Baaten, J.; Hill, R.; Nguyen-Tran, V.; Qiu, M.; Zhang, Y. Q.; Kamireddy, A.; Espinola, S.; Deaton, L.; Ha, S.; Harb, G.; Jia, Y.; Li, J.; Shen, W.; Schumacher, A. M.; Colman, K.; Glynne, R.; Pan, S.; McNamara, P.; Laffitte, B.; Meeusen, S.; Molteni, V.; Loren, J. Selective DYRK1A inhibitor for the treatment of type 1 diabetes: discovery of 6-azaindole derivative GNF2133. J. Med. Chem. 2020, 63, 2958– 2973, DOI: 10.1021/acs.jmedchem.9b01624[ACS Full Text], [CAS], Google Scholar308https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXjtlSqs7g%253D&md5=0ec2402f79b1b3fa338aab9672b8b669Selective DYRK1A Inhibitor for the Treatment of Type 1 Diabetes: Discovery of 6-Azaindole Derivative GNF2133Liu, Yahu A.; Jin, Qihui; Zou, Yefen; Ding, Qiang; Yan, Shanshan; Wang, Zhicheng; Hao, Xueshi; Nguyen, Bao; Zhang, Xiaoyue; Pan, Jianfeng; Mo, Tingting; Jacobsen, Kate; Lam, Thanh; Wu, Tom Y.-H.; Petrassi, H. Michael; Bursulaya, Badry; Di Donato, Michael; Gordon, W. Perry; Liu, Bo; Baaten, Janine; Hill, Robert; Nguyen-Tran, Van; Qiu, Minhua; Zhang, You-Qing; Kamireddy, Anwesh; Espinola, Sheryll; Deaton, Lisa; Ha, Sukwon; Harb, George; Jia, Yong; Li, Jing; Shen, Weijun; Schumacher, Andrew M.; Colman, Karyn; Glynne, Richard; Pan, Shifeng; McNamara, Peter; Laffitte, Bryan; Meeusen, Shelly; Molteni, Valentina; Loren, JonJournal of Medicinal Chemistry (2020), 63 (6), 2958-2973CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Autoimmune deficiency and destruction in either β-cell mass or function can cause insufficient insulin levels and, as a result, hyperglycemia and diabetes. Thus, promoting β-cell proliferation could be one approach toward diabetes intervention. In this report we describe the discovery of a potent and selective DYRK1A inhibitor GNF2133, which was identified through optimization of a 6-azaindole screening hit. In vitro, GNF2133 is able to proliferate both rodent and human β-cells. In vivo, GNF2133 demonstrated significant dose-dependent glucose disposal capacity and insulin secretion in response to glucose-potentiated arginine-induced insulin secretion (GPAIS) challenge in rat insulin promoter and diphtheria toxin A (RIP-DTA) mice. The work described here provides new avenues to disease altering therapeutic interventions in the treatment of type 1 diabetes (T1D).
- 309Siu, M.; Sengupta Ghosh, A.; Lewcock, J. W. Dual leucine zipper kinase inhibitors for the treatment of neurodegeneration. J. Med. Chem. 2018, 61, 8078– 8087, DOI: 10.1021/acs.jmedchem.8b00370[ACS Full Text], [CAS], Google Scholar309https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVGiu7bN&md5=a13dd92c10d63a0a37bc011efb27f67cDual Leucine Zipper Kinase Inhibitors for the Treatment of NeurodegenerationSiu, Michael; Sengupta Ghosh, Arundhati; Lewcock, Joseph W.Journal of Medicinal Chemistry (2018), 61 (18), 8078-8087CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Dual leucine zipper kinase (DLK, MAP3K12) is an essential driver of the neuronal stress response that regulates neurodegeneration in models of acute neuronal injury and chronic neurodegenerative diseases such as Alzheimer's, Parkinson's, and ALS. In this review, we provide an overview of DLK signaling mechanisms and describe selected small mols. that have been utilized to inhibit DLK kinase activity in vivo. These compds. represent valuable tools for understanding the role of DLK signaling and evaluating the potential for DLK inhibition as a therapeutic strategy to prevent neuronal degeneration.
- 310Patel, S.; Cohen, F.; Dean, B. J.; De La Torre, K.; Deshmukh, G.; Estrada, A. A.; Ghosh, A. S.; Gibbons, P.; Gustafson, A.; Huestis, M. P.; Le Pichon, C. E.; Lin, H.; Liu, W.; Liu, X.; Liu, Y.; Ly, C. Q.; Lyssikatos, J. P.; Ma, C.; Scearce-Levie, K.; Shin, Y. G.; Solanoy, H.; Stark, K. L.; Wang, J.; Wang, B.; Zhao, X.; Lewcock, J. W.; Siu, M. Discovery of dual leucine zipper kinase (DLK, MAP3K12) inhibitors with activity in neurodegeneration models. J. Med. Chem. 2015, 58, 401– 418, DOI: 10.1021/jm5013984[ACS Full Text], [CAS], Google Scholar310https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVSjsr3P&md5=8f4ebdbfb0d324a4253bcd832e690a18Discovery of Dual Leucine Zipper Kinase (DLK, MAP3K12) Inhibitors with Activity in Neurodegeneration ModelsPatel, Snahel; Cohen, Frederick; Dean, Brian J.; De La Torre, Kelly; Deshmukh, Gauri; Estrada, Anthony A.; Ghosh, Arundhati Sengupta; Gibbons, Paul; Gustafson, Amy; Huestis, Malcolm P.; Le Pichon, Claire E.; Lin, Han; Liu, Wendy; Liu, Xingrong; Liu, Yichin; Ly, Cuong Q.; Lyssikatos, Joseph P.; Ma, Changyou; Scearce-Levie, Kimberly; Shin, Young G.; Solanoy, Hilda; Stark, Kimberly L.; Wang, Jian; Wang, Bei; Zhao, Xianrui; Lewcock, Joseph W.; Siu, MichaelJournal of Medicinal Chemistry (2015), 58 (1), 401-418CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Dual leucine zipper kinase (DLK, MAP3K12) was recently identified as an essential regulator of neuronal degeneration in multiple contexts. Here the authors describe the generation of potent and selective DLK inhibitors starting from a high-throughput screening hit. Using proposed hinge-binding interactions to infer a binding mode and specific design parameters to optimize for CNS druglike mols., the authors came to focus on the di(pyridin-2-yl)amines because of their combination of desirable potency and good brain penetration following oral dosing. The lead inhibitor GNE-3511 I displayed concn.-dependent protection of neurons from degeneration in vitro and demonstrated dose-dependent activity in two different animal models of disease. These results suggest that specific pharmacol. inhibition of DLK may have therapeutic potential in multiple indications.
- 311Patel, S.; Harris, S. F.; Gibbons, P.; Deshmukh, G.; Gustafson, A.; Kellar, T.; Lin, H.; Liu, X.; Liu, Y.; Liu, Y.; Ma, C.; Scearce-Levie, K.; Ghosh, A. S.; Shin, Y. G.; Solanoy, H.; Wang, J.; Wang, B.; Yin, J.; Siu, M.; Lewcock, J. W. Scaffold-hopping and structure-based discovery of potent, selective, and brain penetrant N-(1H-pyrazol-3-yl)pyridin-2-amine inhibitors of dual Leucine zipper kinase (DLK, MAP3K12). J. Med. Chem. 2015, 58, 8182– 8199, DOI: 10.1021/acs.jmedchem.5b01072[ACS Full Text], [CAS], Google Scholar311https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1Kit7fN&md5=e7b850d7c7d2eac3317b573ace2c6fabScaffold-Hopping and Structure-Based Discovery of Potent, Selective, And Brain Penetrant N-(1H-Pyrazol-3-yl)pyridin-2-amine Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12)Patel, Snahel; Harris, Seth F.; Gibbons, Paul; Deshmukh, Gauri; Gustafson, Amy; Kellar, Terry; Lin, Han; Liu, Xingrong; Liu, Yanzhou; Liu, Yichin; Ma, Changyou; Scearce-Levie, Kimberly; Ghosh, Arundhati Sengupta; Shin, Young G.; Solanoy, Hilda; Wang, Jian; Wang, Bei; Yin, Jianping; Siu, Michael; Lewcock, Joseph W.Journal of Medicinal Chemistry (2015), 58 (20), 8182-8199CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Recent data suggest that inhibition of dual leucine zipper kinase (DLK, MAP3K12) has therapeutic potential for treatment of a no. of indications ranging from acute neuronal injury to chronic neurodegenerative disease. Thus, high demand exists for selective small mol. DLK inhibitors with favorable drug-like properties and good CNS penetration. Herein the authors describe a shape-based scaffold hopping approach to convert pyrimidine 1 to a pyrazole core with improved physicochem. properties. The authors also present the first crystal structures of DLK. By utilizing a combination of property and structure-based design, the authors identified inhibitor I, a potent, selective, and brain-penetrant inhibitor of DLK with activity in an in vivo nerve injury model.
- 312Patel, S.; Meilandt, W. J.; Erickson, R. I.; Chen, J.; Deshmukh, G.; Estrada, A. A.; Fuji, R. N.; Gibbons, P.; Gustafson, A.; Harris, S. F.; Imperio, J.; Liu, W.; Liu, X.; Liu, Y.; Lyssikatos, J. P.; Ma, C.; Yin, J.; Lewcock, J. W.; Siu, M. Selective inhibitors of dual Leucine zipper kinase (DLK, MAP3K12) with activity in a model of Alzheimer’s disease. J. Med. Chem. 2017, 60, 8083– 8102, DOI: 10.1021/acs.jmedchem.7b00843[ACS Full Text], [CAS], Google Scholar312https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFWhsL%252FF&md5=bda6dd84d0c56e3a9c9849c9de69233eSelective Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12) with Activity in a Model of Alzheimer's DiseasePatel, Snahel; Meilandt, William J.; Erickson, Rebecca I.; Chen, Jinhua; Deshmukh, Gauri; Estrada, Anthony A.; Fuji, Reina N.; Gibbons, Paul; Gustafson, Amy; Harris, Seth F.; Imperio, Jose; Liu, Wendy; Liu, Xingrong; Liu, Yichin; Lyssikatos, Joseph P.; Ma, Changyou; Yin, Jianping; Lewcock, Joseph W.; Siu, MichaelJournal of Medicinal Chemistry (2017), 60 (19), 8083-8102CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Significant data exists to suggest that dual leucine zipper kinase (DLK, MAP3K12) is a conserved regulator of neuronal degeneration following neuronal injury and in chronic neurodegenerative disease. Consequently, there is considerable interest in the identification of DLK inhibitors with a profile compatible with development for these indications. Herein, we use structure-based drug design combined with a focus on CNS drug-like properties to generate compds. with superior kinase selectivity and metabolic stability as compared to previously disclosed DLK inhibitors. These compds., exemplified by inhibitor 14, retain excellent CNS penetration and are well tolerated following multiple days of dosing at concns. that exceed those required for DLK inhibition in the brain.
- 313Wu, B.; De, S. K.; Kulinich, A.; Salem, A. F.; Koeppen, J.; Wang, R.; Barile, E.; Wang, S.; Zhang, D.; Ethell, I.; Pellecchia, M. Potent and selective EphA4 agonists for the treatment of ALS. Cell Chem. Biol. 2017, 24, 293– 305, DOI: 10.1016/j.chembiol.2017.01.006[Crossref], [PubMed], [CAS], Google Scholar313https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXisF2isLw%253D&md5=4701fc563841cf233e9e8c8ac7c256f7Potent and Selective EphA4 Agonists for the Treatment of ALSWu, Bainan; De, Surya K.; Kulinich, Anna; Salem, Ahmed F.; Koeppen, Jordan; Wang, Rengang; Barile, Elisa; Wang, Si; Zhang, Dongxiang; Ethell, Iryna; Pellecchia, MaurizioCell Chemical Biology (2017), 24 (3), 293-305CODEN: CCBEBM; ISSN:2451-9448. (Cell Press)Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease that affects motor neurons. Recent studies identified the receptor tyrosine kinase EphA4 as a disease-modifying gene that is crit. for the progression of motor neuron degeneration. We report on the design and characterization of a family of EphA4 targeting agents that bind to its ligand binding domain with nanomolar affinity. The mols. exhibit excellent selectivity and display efficacy in a SOD1 mutant mouse model of ALS. Interestingly, the mols. appear to act as agonists for the receptor in certain surrogate cellular assays. While the exact mechanisms responsible for the therapeutic effect of the new agonists remain to be elucidated, we believe that the described agent represents both an invaluable pharmacol. tool to further decipher the role of the EphA4 in ALS and potentially other human diseases, and a significant stepping stone for the development of novel treatments.
- 314Ziegelbauer, K.; Gantner, F.; Lukacs, N. W.; Berlin, A.; Fuchikami, K.; Niki, T.; Sakai, K.; Inbe, H.; Takeshita, K.; Ishimori, M.; Komura, H.; Murata, T.; Lowinger, T.; Bacon, K. B. A selective novel low-molecular-weight inhibitor of IκB kinase-β (IKK-β) prevents pulmonary inflammation and shows broad anti-inflammatory activity. Br. J. Pharmacol. 2005, 145, 178– 192, DOI: 10.1038/sj.bjp.0706176[Crossref], [PubMed], [CAS], Google Scholar314https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXkt1Shtbc%253D&md5=1cc77dccfe9f693ae5badda3565c634eA selective novel low-molecular-weight inhibitor of IκB kinase-β (IKK-β) prevents pulmonary inflammation and shows broad anti-inflammatory activityZiegelbauer, Karl; Gantner, Florian; Lukacs, Nicholas W.; Berlin, Aaron; Fuchikami, Kinji; Niki, Toshiro; Sakai, Katsuya; Inbe, Hisayo; Takeshita, Keisuke; Ishimori, Mina; Komura, Hiroshi; Murata, Toshiki; Lowinger, Timothy; Bacon, Kevin B.British Journal of Pharmacology (2005), 145 (2), 178-192CODEN: BJPCBM; ISSN:0007-1188. (Nature Publishing Group)Pulmonary inflammatory diseases such as asthma are characterized by chronic, cell-mediated inflammation of the bronchial mucosa. Recruitment and activation of inflammatory cells is orchestrated by a variety of mediators such as cytokines, chemokines, or adhesion mols., the expression of which is regulated via the transcription factor nuclear factor kappa B (NF-κB). NF-κB signaling is controlled by the inhibitor of kappa B kinase complex (IKK), a crit. catalytic subunit of which is IKK-β. We identified Compd. A (7-[2-(cyclopropylmethoxy)6-hydroxyphenyl]-5-[(3S)-3-piperidinyl]-1,4-dihydro-2H-pyrido[2,3,-d][1,3]oxazin-2-one hydrochloride) as a small-mol., ATP-competitive inhibitor selectively targeting IKK-β kinase activity with a Ki value of 2 nM. Compd. A inhibited stress-induced NF-κB transactivation, chemokine-, cytokine-, and adhesion mol. expression, and T- and B-cell proliferation. Compd. A is orally bioavailable and inhibited the release of LPS-induced TNF-α in rodents. In mice Compd. A inhibited cockroach allergen-induced airway inflammation and hyperreactivity and efficiently abrogated leukocyte trafficking induced by carrageenan in mice or by ovalbumin in a rat model of airway inflammation. Compd. A was well tolerated by rodents over 3 wk without affecting wt. gain. Furthermore, in mice Compd. A suppressed edema formation in response to arachidonic acid, phorbol ester, or edema induced by delayed-type hypersensitivity. These data suggest that IKK-β inhibitors offer an effective therapeutic approach for inhibiting chronic pulmonary inflammation.
- 315Li, J.; Dong, R.; Yu, J.; Yi, S.; Da, J.; Yu, F.; Zha, Y. Inhibitor of IGF1 receptor alleviates the inflammation process in the diabetic kidney mouse model without activating SOCS2. Drug Des., Dev. Ther. 2018, 12, 2887– 2896, DOI: 10.2147/DDDT.S171638[Crossref], [PubMed], [CAS], Google Scholar315https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhslGru7%252FO&md5=739939a620fedf78ec8e09e1349fa43aInhibitor of IG F1 receptor alleviates the inflammation process in the diabetic kidney mouse model without activating SOCS2Li, Jiayu; Dong, Rong; Yu, Jiali; Yi, Sun; Da, Jingjing; Yu, Fuxun; Zha, YanDrug Design, Development and Therapy (2018), 12 (), 2887-2896CODEN: DDDTAQ; ISSN:1177-8881. (Dove Medical Press Ltd.)Objective: To explore the anti-inflammatory mechanism of IGF1R inhibitor in diabetic nephropathy. Methods: C57/BL6 mice were reared with high-fat diet for 8 wk, then were injected 30 mg/kg streptozotocin i.p. to induce type 2 diabetes. After 8 wk, the type 2 diabetes nephropathy model was successfully set up the different drugs were administrated to mice with diabetes (insulin 1-2 U/day, benazepril 10 mg/kg per day intragastrically, IGF-1R inhibitor 30 mg/kg per day intragastrically). After 8 wk drugs administration, all mice were collected the kidney tissue, measured levels of inflammatory factor (F4/80, TLR4and CD68) and fibrosis markers(αSMA, E-cadherin and SR) using immunohistochem. and in situ hybridization. Results: The type 2 diabetes nephropathy model was built successfully, which along with increased urinary protein excretion rate and increased inflammatory infiltration, and the correlation was characterized by increased CD68+, F4/80+ cells and increased TLR4, αSMA, SR expression. IGF-1R inhibitors reversed this changes, but benazepril and insulin were without significant changes. The insulin decreased the expression level of IGF-1, and increased the levels of suppressor of cytokine signaling 2 (SOCS2). Benazepril and IGF-1R inhibitor were no significant changes like insulin. Conclusion: Inhibition of IGF1R was a more effective choice for inflammation treatment than Ben or Ins in diabetic kidney disease (DKD). The IGF1R inhibitor blocked pathol. changes induced by the over-expression of IGF1 in DKD without up-regulating SOCS2 protein levels.
- 316Zapf, C. W.; Gerstenberger, B. S.; Xing, L.; Limburg, D. C.; Anderson, D. R.; Caspers, N.; Han, S.; Aulabaugh, A.; Kurumbail, R.; Shakya, S.; Li, X.; Spaulding, V.; Czerwinski, R. M.; Seth, N.; Medley, Q. G. Covalent inhibitors of interleukin-2 inducible T cell kinase (itk) with nanomolar potency in a whole-blood assay. J. Med. Chem. 2012, 55, 10047– 10063, DOI: 10.1021/jm301190s[ACS Full Text], [CAS], Google Scholar316https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFOlsbnP&md5=7e39a17151dc9493d13439bc48fa83a3Covalent Inhibitors of Interleukin-2 Inducible T Cell Kinase (Itk) with Nanomolar Potency in a Whole-Blood AssayZapf, Christoph W.; Gerstenberger, Brian S.; Xing, Li; Limburg, David C.; Anderson, David R.; Caspers, Nicole; Han, Seungil; Aulabaugh, Ann; Kurumbail, Ravi; Shakya, Subarna; Li, Xin; Spaulding, Vikki; Czerwinski, Robert M.; Seth, Nilufer; Medley, Quintus G.Journal of Medicinal Chemistry (2012), 55 (22), 10047-10063CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)We wish to report a strategy that targets interleukin-2 inducible T cell kinase (Itk) with covalent inhibitors. Thus far, covalent inhibition of Itk has not been disclosed in the literature. Structure-based drug design was utilized to achieve low nanomolar potency of the disclosed series even at high ATP concns. Kinetic measurements confirmed an irreversible binding mode with off-rate half-lives exceeding 24 h and moderate on-rates. The analogs are highly potent in a cellular IP1 assay as well as in a human whole-blood (hWB) assay. Despite a half-life of approx. 2 h in resting primary T cells, the covalent inhibition of Itk resulted in functional silencing of the TCR pathway for more than 24 h. This prolonged effect indicates that covalent inhibition is a viable strategy to target the inactivation of Itk.
- 317Burch, J. D.; Lau, K.; Barker, J. J.; Brookfield, F.; Chen, Y.; Chen, Y.; Eigenbrot, C.; Ellebrandt, C.; Ismaili, M. H. A.; Johnson, A.; Kordt, D.; MacKinnon, C. H.; McEwan, P. A.; Ortwine, D. F.; Stein, D. B.; Wang, X.; Winkler, D.; Yuen, P.-W.; Zhang, Y.; Zarrin, A. A.; Pei, Z. Property- and structure-guided discovery of a tetrahydroindazole series of interleukin-2 inducible T-cell kinase inhibitors. J. Med. Chem. 2014, 57, 5714– 5727, DOI: 10.1021/jm500550e[ACS Full Text], [CAS], Google Scholar317https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXps1Srtrs%253D&md5=636420d73f6ad55bf5391b6c6aeb3dbdProperty- and Structure-Guided Discovery of a Tetrahydroindazole Series of Interleukin-2 Inducible T-Cell Kinase InhibitorsBurch, Jason D.; Lau, Kevin; Barker, John J.; Brookfield, Fred; Chen, Yong; Chen, Yuan; Eigenbrot, Charles; Ellebrandt, Claire; Ismaili, M. Hicham A.; Johnson, Adam; Kordt, Daniel; MacKinnon, Colin H.; McEwan, Paul A.; Ortwine, Daniel F.; Stein, Daniel B.; Wang, Xiaolu; Winkler, Dirk; Yuen, Po-Wai; Zhang, Yamin; Zarrin, Ali A.; Pei, ZhonghuaJournal of Medicinal Chemistry (2014), 57 (13), 5714-5727CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Interleukin-2 inducible T-cell kinase (ITK), a member of the Tec family of tyrosine kinases, plays a major role in T-cell signaling downstream of the T-cell receptor (TCR), and considerable efforts have been directed toward discovery of ITK-selective inhibitors as potential treatments of inflammatory disorders such as asthma. Using a previously disclosed indazole series of inhibitors as a starting point, and using x-ray crystallog. and soly. forecast index (SFI) as guides, we evolved a series of tetrahydroindazole inhibitors with improved potency, selectivity, and pharmaceutical properties. Highlights include identification of a selectivity pocket above the ligand plane, and identification of appropriate lipophilic substituents to occupy this space. This effort culminated in identification of a potent and selective ITK inhibitor (GNE-9822) with good ADME properties in preclin. species.
- 318Burch, J. D.; Barrett, K.; Chen, Y.; DeVoss, J.; Eigenbrot, C.; Goldsmith, R.; Ismaili, M. H. A.; Lau, K.; Lin, Z.; Ortwine, D. F.; Zarrin, A. A.; McEwan, P. A.; Barker, J. J.; Ellebrandt, C.; Kordt, D.; Stein, D. B.; Wang, X.; Chen, Y.; Hu, B.; Xu, X.; Yuen, P.-W.; Zhang, Y.; Pei, Z. Tetrahydroindazoles as interleukin-2 inducible t-cell kinase inhibitors. Part II. Second-generation analogues with enhanced potency, selectivity, and pharmacodynamic modulation in vivo. J. Med. Chem. 2015, 58, 3806– 3816, DOI: 10.1021/jm501998m[ACS Full Text], [CAS], Google Scholar318https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXlvVaktbo%253D&md5=59a2cd1c2c9d368f9b49344af9b75545Tetrahydroindazoles as Interleukin-2 Inducible T-Cell Kinase Inhibitors. Part II. Second-Generation Analogues with Enhanced Potency, Selectivity, and Pharmacodynamic Modulation in VivoBurch, Jason D.; Barrett, Kathy; Chen, Yuan; DeVoss, Jason; Eigenbrot, Charles; Goldsmith, Richard; Ismaili, M. Hicham A.; Lau, Kevin; Lin, Zhonghua; Ortwine, Daniel F.; Zarrin, Ali A.; McEwan, Paul A.; Barker, John J.; Ellebrandt, Claire; Kordt, Daniel; Stein, Daniel B.; Wang, Xiaolu; Chen, Yong; Hu, Baihua; Xu, Xiaofeng; Yuen, Po-Wai; Zhang, Yamin; Pei, ZhonghuaJournal of Medicinal Chemistry (2015), 58 (9), 3806-3816CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The medicinal chem. community has directed considerable efforts toward the discovery of selective inhibitors of interleukin-2 inducible T-cell kinase (ITK), given its role in T-cell signaling downstream of the T-cell receptor (TCR) and the implications of this target for inflammatory disorders such as asthma. The authors have previously disclosed a structure- and property-guided lead optimization effort which resulted in the discovery of a new series of tetrahydroindazole-contg. selective ITK inhibitors. Herein the authors disclose further optimization of this series that resulted in further potency improvements, reduced off-target receptor binding liabilities, and reduced cytotoxicity. Specifically, the authors have identified a correlation between the basicity of solubilizing elements in the ITK inhibitors and off-target antiproliferative effects, which was exploited to reduce cytotoxicity while maintaining kinase selectivity. Optimized analogs, e.g. I, were shown to reduce IL-2 and IL-13 prodn. in vivo following oral or i.p. dosing in mice.
- 319Heifetz, A.; Trani, G.; Aldeghi, M.; MacKinnon, C. H.; McEwan, P. A.; Brookfield, F. A.; Chudyk, E. I.; Bodkin, M.; Pei, Z.; Burch, J. D.; Ortwine, D. F. Fragment molecular orbital method applied to lead optimization of novel interleukin-2 inducible T-cell kinase (ITK) inhibitors. J. Med. Chem. 2016, 59, 4352– 4363, DOI: 10.1021/acs.jmedchem.6b00045[ACS Full Text], [CAS], Google Scholar319https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xjs12jt70%253D&md5=b0958d9c29f7d61aadcc730ac00e8f90Fragment Molecular Orbital Method Applied to Lead Optimization of Novel Interleukin-2 Inducible T-Cell Kinase (ITK) InhibitorsHeifetz, Alexander; Trani, Giancarlo; Aldeghi, Matteo; MacKinnon, Colin H.; McEwan, Paul A.; Brookfield, Frederick A.; Chudyk, Ewa I.; Bodkin, Mike; Pei, Zhonghua; Burch, Jason D.; Ortwine, Daniel F.Journal of Medicinal Chemistry (2016), 59 (9), 4352-4363CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Inhibition of inducible T-cell kinase (ITK), a nonreceptor tyrosine kinase, may represent a novel treatment for allergic asthma. In our previous reports, we described the discovery of sulfonylpyridine (SAP), benzothiazole (BZT), indazole (IND), and tetrahydroindazole (THI) series as novel ITK inhibitors and how computational tools such as dihedral scans and docking were used to support this process. X-ray crystallog. and modeling were applied to provide essential insight into ITK-ligand interactions. However, "visual inspection" traditionally used for the rationalization of protein-ligand affinity cannot always explain the full complexity of the mol. interactions. The fragment MO (FMO) quantum-mech. (QM) method provides a complete list of the interactions formed between the ligand and protein that are often omitted from traditional structure-based descriptions. FMO methodol. was successfully used as part of a rational structure-based drug design effort to improve the ITK potency of high-throughput screening hits, ultimately delivering ligands with potency in the subnanomolar range.
- 320Yin, Y.; Zheng, K.; Eid, N.; Howard, S.; Jeong, J. H.; Yi, F.; Guo, J.; Park, C. M.; Bibian, M.; Wu, W.; Hernandez, P.; Park, H.; Wu, Y.; Luo, J. L.; LoGrasso, P. V.; Feng, Y. Bis-aryl urea derivatives as potent and selective LIM kinase (Limk) inhibitors. J. Med. Chem. 2015, 58, 1846– 1861, DOI: 10.1021/jm501680m[ACS Full Text], [CAS], Google Scholar320https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVWgtb4%253D&md5=67352d15ab435e75f561552f283b29b9Bis-aryl Urea Derivatives as Potent and Selective LIM Kinase (Limk) InhibitorsYin, Yan; Zheng, Ke; Eid, Nibal; Howard, Shannon; Jeong, Ji-Hak; Yi, Fei; Guo, Jia; Park, Chul Min; Bibian, Mathieu; Wu, Weilin; Hernandez, Pamela; Park, HaJeung; Wu, Yuntao; Luo, Jun-Li; LoGrasso, Philip V.; Feng, YangboJournal of Medicinal Chemistry (2015), 58 (4), 1846-1861CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The discovery/optimization of bis-aryl ureas as Limk inhibitors to obtain high potency and selectivity and appropriate pharmacokinetic properties through systematic SAR studies is reported. Docking studies supported the obsd. SAR. Optimized Limk inhibitors had high biochem. potency (IC50 < 25 nM), excellent selectivity against ROCK and JNK kinases (>400-fold), potent inhibition of cofilin phosphorylation in A7r5, PC-3, and CEM-SS T cells (IC50 < 1 μM), and good in vitro and in vivo pharmacokinetic properties. In the profiling against a panel of 61 kinases, compd. I at 1 μM inhibited only Limk1 and STK16 with ≥80% inhibition. Compds. I and II were highly efficient in inhibiting cell-invasion/migration in PC-3 cells. In addn., compd. III was demonstrated to be effective on reducing intraocular pressure on rat eyes. Taken together, these data demonstrated that the authors had developed a novel class of bis-aryl urea derived potent and selective Limk inhibitors.
- 321Chang, Y.; Lu, X.; Shibu, M. A.; Dai, Y. B.; Luo, J.; Zhang, Y.; Li, Y.; Zhao, P.; Zhang, Z.; Xu, Y.; Tu, Z. C.; Zhang, Q. W.; Yun, C. H.; Huang, C. Y.; Ding, K. Structure based design of N-(3-((1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)benzenesulfonamides as selective Leucine-zipper and Sterile-α motif kinase (ZAK) inhibitors. J. Med. Chem. 2017, 60, 5927– 5932, DOI: 10.1021/acs.jmedchem.7b00572[ACS Full Text], [CAS], Google Scholar321https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXpt1Kntb4%253D&md5=897a22435eaf2f7721813f23eb40a62aStructure Based Design of N-(3-(1H-Pyrazolo[3,4-b]pyridin-5-yl)ethynyl)benzenesulfonamides as Selective Leucine-Zipper and Sterile-α Motif Kinase (ZAK) InhibitorsChang, Yu; Lu, Xiaoyun; Shibu, Marthandam Asokan; Dai, Yi-Bo; Luo, Jinfeng; Zhang, Yan; Li, Yingjun; Zhao, Peng; Zhang, Zhang; Xu, Yong; Tu, Zheng-Chao; Zhang, Qing-Wen; Yun, Cai-Hong; Huang, Chih-Yang; Ding, KeJournal of Medicinal Chemistry (2017), 60 (13), 5927-5932CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of N-(3-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)benzenesulfonamides were designed as the first class of highly selective ZAK inhibitors. The representative compd. I strongly inhibits the kinase activity of ZAK with an IC50 of 3.3 nM and dose-dependently suppresses the activation of ZAK downstream signals in vitro and in vivo, while it is significantly less potent for the majority of 403 nonmutated kinases evaluated. Compd. I also exhibits orally therapeutic effects on cardiac hypertrophy in a spontaneous hypertensive rat model.
- 322Yang, J.; Shibu, M. A.; Kong, L.; Luo, J.; BadrealamKhan, F.; Huang, Y.; Tu, Z. C.; Yun, C. H.; Huang, C. Y.; Ding, K.; Lu, X. Design, synthesis, and structure-activity relationships of 1,2,3-triazole benzenesulfonamides as new selective Leucine-zipper and Sterile-α motif kinase (ZAK) inhibitors. J. Med. Chem. 2020, 63, 2114– 2130, DOI: 10.1021/acs.jmedchem.9b00664[ACS Full Text], [CAS], Google Scholar322https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtV2ltr7P&md5=30adc89c957005c96deb7fdbb871065bDesign, Synthesis, and Structure-Activity Relationships of 1,2,3-Triazole Benzenesulfonamides as New Selective Leucine-Zipper and Sterile-α Motif Kinase (ZAK) InhibitorsYang, Jianzhang; Shibu, Marthandam Asokan; Kong, Lulu; Luo, Jinfeng; BadrealamKhan, Farheen; Huang, Yanhui; Tu, Zheng-Chao; Yun, Cai-Hong; Huang, Chih-Yang; Ding, Ke; Lu, XiaoyunJournal of Medicinal Chemistry (2020), 63 (5), 2114-2130CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)ZAK is a new promising target for discovery of drugs with activity against antihypertrophic cardiomyopathy (HCM). A series of 1,2,3-triazole benzenesulfonamides were designed and synthesized as selective ZAK inhibitors. One of these compds., N-(2,4-Difluoro-3-(4-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-1,2,3-triazol-1-yl)phenyl)-[1,1'-biphenyl]-3-sulfonamide binds tightly to ZAK protein (Kd = 8.0 nM) and potently suppresses the kinase function of ZAK with single-digit nM (IC50 = 4.0 nM) and exhibits excellent selectivity in a KINOMEscan screening platform against a panel of 403 wild-type kinases. This compd. dose dependently blocks p38/GATA-4 and JNK/c-Jun signaling and demonstrates promising in vivo anti-HCM efficacy upon oral administration in a spontaneous hypertensive rat (SHR) model. Compd. N-(2,4-Difluoro-3-(4-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-1,2,3-triazol-1-yl)phenyl)-[1,1'-biphenyl]-3-sulfonamide may serve as a lead compd. for new anti-HCM drug discovery.
- 323Goodfellow, V. S.; Loweth, C. J.; Ravula, S. B.; Wiemann, T.; Nguyen, T.; Xu, Y.; Todd, D. E.; Sheppard, D.; Pollack, S.; Polesskaya, O.; Marker, D. F.; Dewhurst, S.; Gelbard, H. A. Discovery, synthesis, and characterization of an orally bioavailable, brain penetrant inhibitor of mixed lineage kinase 3. J. Med. Chem. 2013, 56, 8032– 8048, DOI: 10.1021/jm401094t[ACS Full Text], [CAS], Google Scholar323https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVGjtrfK&md5=53cb667f098b4de13a3a96b92cd546bfDiscovery, Synthesis, and Characterization of an Orally Bioavailable, Brain Penetrant Inhibitor of Mixed Lineage Kinase 3Goodfellow, Val S.; Loweth, Colin J.; Ravula, Satheesh B.; Wiemann, Torsten; Nguyen, Thong; Xu, Yang; Todd, Daniel E.; Sheppard, David; Pollack, Scott; Polesskaya, Oksana; Marker, Daniel F.; Dewhurst, Stephen; Gelbard, Harris A.Journal of Medicinal Chemistry (2013), 56 (20), 8032-8048CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Inhibition of mixed lineage kinase 3 (MLK3) is a potential strategy for treatment of Parkinson's disease and HIV-1 assocd. neurocognitive disorders (HAND), requiring an inhibitor that can achieve significant brain concn. levels. We report here URMC-099 (1) an orally bioavailable (F = 41%), potent (IC50 = 14 nM) MLK3 inhibitor with excellent brain exposure in mouse PK models and minimal interference with key human CYP450 enzymes or hERG channels. The compd. inhibits LPS-induced TNFα release in microglial cells, HIV-1 Tat-induced release of cytokines in human monocytes and up-regulation of phospho-JNK in Tat-injected brains of mice. Compd. 1 likely functions in HAND preclin. models by inhibiting multiple kinase pathways, including MLK3 and LRRK2 (IC50 = 11 nM). We compare the kinase specificity and BBB penetration of 1 with CEP-1347 (2). Compd. 1 is well tolerated, with excellent in vivo activity in HAND models, and is under investigation for further development.
- 324Zhang, W.; McIver, A. L.; Stashko, M. A.; DeRyckere, D.; Branchford, B. R.; Hunter, D.; Kireev, D.; Miley, M. J.; Norris-Drouin, J.; Stewart, W. M.; Lee, M.; Sather, S.; Zhou, Y.; Di Paola, J. A.; Machius, M.; Janzen, W. P.; Earp, H. S.; Graham, D. K.; Frye, S. V.; Wang, X. Discovery of Mer specific tyrosine kinase inhibitors for the treatment and prevention of thrombosis. J. Med. Chem. 2013, 56, 9693– 9700, DOI: 10.1021/jm4013888[ACS Full Text], [CAS], Google Scholar324https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslOms7rK&md5=07f0b637d009061599c05caaf503372eDiscovery of Mer Specific Tyrosine Kinase Inhibitors for the Treatment and Prevention of ThrombosisZhang, Weihe; McIver, Andrew L.; Stashko, Michael A.; DeRyckere, Deborah; Branchford, Brian R.; Hunter, Debra; Kireev, Dmitri; Miley, Michael J.; Norris-Drouin, Jacqueline; Stewart, Wendy M.; Lee, Minjung; Sather, Susan; Zhou, Yingqiu; Di Paola, Jorge A.; Machius, Mischa; Janzen, William P.; Earp, H. Shelton; Graham, Douglas K.; Frye, Stephen V.; Wang, XiaodongJournal of Medicinal Chemistry (2013), 56 (23), 9693-9700CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The role of Mer kinase in regulating the second phase of platelet activation generates an opportunity to use Mer inhibitors for preventing thrombosis with diminished likelihood for bleeding as compared to current therapies. Toward this end, we have discovered a novel, Mer kinase specific substituted-pyrimidine scaffold using a structure-based drug design and a pseudo ring replacement strategy. The cocrystal structure of Mer with two compds. possessing distinct activity have been detd. Subsequent SAR studies identified compd. I (UNC2881) as a lead compd. for in vivo evaluation. When applied to live cells, I inhibits steady-state Mer kinase phosphorylation with an IC50 value of 22 nM. Treatment with I is also sufficient to block EGF-mediated stimulation of a chimeric receptor contg. the intracellular domain of Mer fused to the extracellular domain of EGFR. In addn., I potently inhibits collagen-induced platelet aggregation, suggesting that this class of inhibitors may have utility for prevention and/or treatment of pathol. thrombosis.
- 325Dow, R. L.; Ammirati, M.; Bagley, S. W.; Bhattacharya, S. K.; Buckbinder, L.; Cortes, C.; El-Kattan, A. F.; Ford, K.; Freeman, G. B.; Guimarães, C. R. W.; Liu, S.; Niosi, M.; Skoura, A.; Tess, D. 2-Aminopyridine-based Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) inhibitors: assessment of mechanism-based safety. J. Med. Chem. 2018, 61, 3114– 3125, DOI: 10.1021/acs.jmedchem.8b00152[ACS Full Text], [CAS], Google Scholar325https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXlvVKnsLg%253D&md5=5ade14664351cabbd0a023b86a5d79972-Aminopyridine-Based Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 (MAP4K4) Inhibitors: Assessment of Mechanism-Based SafetyDow, Robert L.; Ammirati, Mark; Bagley, Scott W.; Bhattacharya, Samit K.; Buckbinder, Leonard; Cortes, Christian; El-Kattan, Ayman F.; Ford, Kristen; Freeman, Gary B.; Guimaraes, Cristiano R. W.; Liu, Shenping; Niosi, Mark; Skoura, Athanasia; Tess, DavidJournal of Medicinal Chemistry (2018), 61 (7), 3114-3125CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Studies have linked the serine-threonine kinase MAP4K4 to the regulation of a no. of biol. processes and/or diseases, including diabetes, cancer, inflammation, and angiogenesis. With a majority of the members of our lead series (e.g., 1) suffering from time-dependent inhibition (TDI) of CYP3A4, we sought design avenues that would eliminate this risk. One such approach arose from the observation that carboxylic acid-based intermediates employed in our discovery efforts retained high MAP4K4 inhibitory potency and were devoid of the TDI risk. The medicinal chem. effort that led to the discovery of this central nervous system-impaired inhibitor together with its preclin. safety profile is described.
- 326Crespo, R. A.; Dang, Q.; Zhou, N. E.; Guthrie, L. M.; Snavely, T. C.; Dong, W.; Loesch, K. A.; Suzuki, T.; You, L.; Wang, W.; O’Malley, T.; Parish, T.; Olsen, D. B.; Sacchettini, J. C. Structure-guided drug design of 6-substituted adenosine analogues as potent inhibitors of mycobacterium tuberculosis adenosine kinase. J. Med. Chem. 2019, 62, 4483– 4499, DOI: 10.1021/acs.jmedchem.9b00020[ACS Full Text], [CAS], Google Scholar326https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXns12isLo%253D&md5=b703c0a70784d4c9d922f12de2224081Structure-Guided Drug Design of 6-Substituted Adenosine Analogues as Potent Inhibitors of Mycobacterium tuberculosis Adenosine KinaseCrespo, Roberto A.; Dang, Qun; Zhou, Nian E.; Guthrie, Liam M.; Snavely, Thomas C.; Dong, Wen; Loesch, Kimberly A.; Suzuki, Takao; You, Lanying; Wang, Wei; O'Malley, Theresa; Parish, Tanya; Olsen, David B.; Sacchettini, James C.Journal of Medicinal Chemistry (2019), 62 (9), 4483-4499CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Mycobacterium tuberculosis adenosine kinase (MtbAdoK) is an essential enzyme of Mtb and forms part of the purine salvage pathway within mycobacteria. Evidence suggests that the purine salvage pathway might play a crucial role in Mtb survival and persistence during its latent phase of infection. In these studies, we adopted a structural approach to the discovery, structure-guided design, and synthesis of a series of adenosine analogs that displayed inhibition consts. ranging from 5 to 120 nM against the enzyme. Two of these compds. exhibited low micromolar activity against Mtb with half maximal effective inhibitory concns. of 1.7 and 4.0 μM. Our selectivity and preliminary pharmacokinetic studies showed that the compds. possess a higher degree of specificity against MtbAdoK when compared with the human counterpart and are well tolerated in rodents, resp. Finally, crystallog. studies showed the mol. basis of inhibition, potency, and selectivity and revealed the presence of a potentially therapeutically relevant cavity unique to the MtbAdoK homodimer.
- 327Song, L.; Merceron, R.; Gracia, B.; Quintana, A. L.; Risseeuw, M. D. P.; Hulpia, F.; Cos, P.; Ainsa, J. A.; Munier-Lehmann, H.; Savvides, S. N.; Van Calenbergh, S. Structure guided lead generation toward Nonchiral M. Tuberculosis thymidylate kinase inhibitors. J. Med. Chem. 2018, 61, 2753– 2775, DOI: 10.1021/acs.jmedchem.7b01570[ACS Full Text], [CAS], Google Scholar327https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjvFWnsr4%253D&md5=c4b195c0bb6969ad71abece65c82bd4aStructure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase InhibitorsSong, Lijun; Merceron, Romain; Gracia, Begona; Quintana, Ainhoa Lucia; Risseeuw, Martijn D. P.; Hulpia, Fabian; Cos, Paul; Ainsa, Jose A.; Munier-Lehmann, Helene; Savvides, Savvas N.; Van Calenbergh, SergeJournal of Medicinal Chemistry (2018), 61 (7), 2753-2775CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)In recent years, thymidylate kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, the authors have built upon the authors' previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK (MtTMPK) inhibitors, and reported here the design of a novel series of non-nucleoside inhibitors of MtTMPK. The inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure-activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, expts. with efflux pump inhibitors and efflux pump knockout mutants were performed. The min. inhibitory concns. of particular inhibitors increased significantly when detd. for the efflux pump mmr knockout mutant, which partly explains the obsd. dissonance.
- 328Sala, M.; Hollinger, K. R.; Thomas, A. G.; Dash, R. P.; Tallon, C.; Veeravalli, V.; Lovell, L.; Kogler, M.; Hrebabecky, H.; Prochazkova, E.; Nesuta, O.; Donoghue, A.; Lam, J.; Rais, R.; Rojas, C.; Slusher, B. S.; Nencka, R. Novel human neutral sphingomyelinase 2 inhibitors as potential therapeutics for Alzheimer’s disease. J. Med. Chem. 2020, 63, 6028– 6056, DOI: 10.1021/acs.jmedchem.0c00278[ACS Full Text], [CAS], Google Scholar328https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXnt12ru7k%253D&md5=ae913fb6068ef7d230f0ef4a49d25975Novel Human Neutral Sphingomyelinase 2 Inhibitors as Potential Therapeutics for Alzheimer's DiseaseSala, Michal; Hollinger, Kristen R.; Thomas, Ajit G.; Dash, Ranjeet P.; Tallon, Carolyn; Veeravalli, Vijayabhaskar; Lovell, Lyndah; Kogler, Martin; Hrebabecky, Hubert; Prochazkova, Eliska; Nesuta, Ondrej; Donoghue, Amanda; Lam, Jenny; Rais, Rana; Rojas, Camilo; Slusher, Barbara S.; Nencka, RadimJournal of Medicinal Chemistry (2020), 63 (11), 6028-6056CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Neutral sphingomyelinase 2 (nSMase2) catalyzes the cleavage of sphingomyelin to phosphorylcholine and ceramide, an essential step in the formation and release of exosomes from cells that is crit. for intracellular communication. Chronic increase of brain nSMase2 activity and related exosome release has been implicated in various pathol. processes, including the progression of Alzheimer's disease (AD), making nSMase2 a viable therapeutic target. Recently, we identified phenyl(R)-(1-(3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b] pyridazin-8-yl) pyrrolidin-3-yl)-carbamate 1 (PDDC)(I), the first nSMase2 inhibitor which possesses both favorable pharmacodynamics and pharmacokinetic (PK) parameters, including substantial oral bioavailability, brain penetration and significant inhibition of exosome release from the brain in vivo. Herein we demonstrate efficacy of 1 (PDDC) in a mouse model of AD and detail extensive structure-activity relationship (SAR) studies with 70 analogs, unveiling several that exert similar or higher activity against nSMase2 with favorable pharmacokinetic properties.
- 329Jimenez, J. M.; Boyall, D.; Brenchley, G.; Collier, P. N.; Davis, C. J.; Fraysse, D.; Keily, S. B.; Henderson, J.; Miller, A.; Pierard, F.; Settimo, L.; Twin, H. C.; Bolton, C. M.; Curnock, A. P.; Chiu, P.; Tanner, A. J.; Young, S. Design and optimization of selective protein kinase C theta (PKCtheta) inhibitors for the treatment of autoimmune diseases. J. Med. Chem. 2013, 56, 1799– 1810, DOI: 10.1021/jm301465a[ACS Full Text], [CAS], Google Scholar329https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXitl2ksb4%253D&md5=6f479112ea9234b9d59e3354da2c11e8Design and Optimization of Selective Protein Kinase C θ (PKCθ) Inhibitors for the Treatment of Autoimmune DiseasesJimenez, Juan-Miguel; Boyall, Dean; Brenchley, Guy; Collier, Philip N.; Davis, Christopher J.; Fraysse, Damien; Keily, Shazia B.; Henderson, Jaclyn; Miller, Andrew; Pierard, Francoise; Settimo, Luca; Twin, Heather C.; Bolton, Claire M.; Curnock, Adam P.; Chiu, Peter; Tanner, Adam J.; Young, StephenJournal of Medicinal Chemistry (2013), 56 (5), 1799-1810CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Protein kinase C θ (PKCθ) has a central role in T cell activation and survival; however, the dependency of T cell responses to the inhibition of this enzyme appears to be dictated by the nature of the antigen and by the inflammatory environment. Studies in PKCθ-deficient mice have demonstrated that while antiviral responses are PKCθ-independent, T cell responses assocd. with autoimmune diseases are PKCθ-dependent. Thus, potent and selective inhibition of PKCθ is expected to block autoimmune T cell responses without compromising antiviral immunity. Herein, we describe the development of potent and selective PKCθ inhibitors, which show exceptional potency in cells and in vivo. By use of a structure based rational design approach, a 1000-fold improvement in potency and 76-fold improvement in selectivity over closely related PKC isoforms such as PKCδ were obtained from the initial HTS hit I, together with a big improvement in lipophilic efficiency (LiPE).
- 330George, D. M.; Breinlinger, E. C.; Argiriadi, M. A.; Zhang, Y.; Wang, J.; Bansal-Pakala, P.; Duignan, D. B.; Honore, P.; Lang, Q.; Mittelstadt, S.; Rundell, L.; Schwartz, A.; Sun, J.; Edmunds, J. J. Optimized protein kinase Ctheta (PKCtheta) inhibitors reveal only modest anti-inflammatory efficacy in a rodent model of arthritis. J. Med. Chem. 2015, 58, 333– 346, DOI: 10.1021/jm5013006[ACS Full Text], [CAS], Google Scholar330https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1Wlu7zM&md5=8737f7f41b661f84117fdca365fc9f9dOptimized Protein Kinase Cθ (PKCθ) Inhibitors Reveal Only Modest Anti-inflammatory Efficacy in a Rodent Model of ArthritisGeorge, Dawn M.; Breinlinger, Eric C.; Argiriadi, Maria A.; Zhang, Yang; Wang, Jianfei; Bansal-Pakala, Pratima; Duignan, David B.; Honore, Prisca; Lang, QingYu; Mittelstadt, Scott; Rundell, Lian; Schwartz, Annette; Sun, Jiakang; Edmunds, Jeremy J.Journal of Medicinal Chemistry (2015), 58 (1), 333-346CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The authors previously demonstrated that selective inhibition of protein kinase Cθ (PKCθ) with a triazinone lead resulted in dose-dependent redn. of paw swelling in a mouse model of arthritis. However, a high concn. was required for efficacy, thus providing only a minimal safety window. Herein the authors describe a strategy to deliver safer compds. based on the hypothesis that optimization of potency in concert with good oral pharmacokinetic (PK) properties would enable in vivo efficacy at reduced exposures, resulting in an improved safety window. Ultimately, transformation of the triazinone lead yielded analogs that demonstrated excellent potency and PK properties and fully inhibited IL-2 prodn. in an acute model. In spite of good exposure, twice-a-day treatment with I in the glucose-6-phosphate isomerase chronic in vivo mouse model of arthritis yielded only moderate efficacy. On the basis of the exposure achieved, the authors conclude that PKCθ inhibition alone is insufficient for complete efficacy in this rodent arthritis model.
- 331Abdel-Halim, M.; Diesel, B.; Kiemer, A. K.; Abadi, A. H.; Hartmann, R. W.; Engel, M. Discovery and optimization of 1,3,5-trisubstituted pyrazolines as potent and highly selective allosteric inhibitors of protein kinase C-zeta. J. Med. Chem. 2014, 57, 6513– 6530, DOI: 10.1021/jm500521n[ACS Full Text], [CAS], Google Scholar331https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht1WmsrzJ&md5=95c3f2c59aabf54afb97632e8bd8ff7cDiscovery and Optimization of 1,3,5-Trisubstituted Pyrazolines as Potent and Highly Selective Allosteric Inhibitors of Protein Kinase C-ζAbdel-Halim, Mohammad; Diesel, Britta; Kiemer, Alexandra K.; Abadi, Ashraf H.; Hartmann, Rolf W.; Engel, MatthiasJournal of Medicinal Chemistry (2014), 57 (15), 6513-6530CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)There is increasing evidence that the atypical protein kinase C, PKCζ, might be a therapeutic target in pulmonary and hepatic inflammatory diseases. However, targeting the highly conserved ATP-binding pocket in the catalytic domain held little promise to achieve selective inhibition. In the present study, the authors introduce 1,3,5-trisubstituted pyrazolines, e.g. I [R1 = 4-HO, 4-F, 4-Cl, etc.; R2 = Me, Ph, t-Bu, etc.; R3 = H, 4-Cl, 4-Br, etc.; R4 = H, Me] as potent and selective allosteric PKCζ inhibitors. The rigid scaffold offered many sites for modification, all acting as hot spots for improving activity, and gave rise to sharp structure-activity relationships. Targeting of PKCζ in cells was confirmed by reporter gene assay, transfection assays, and Western blotting. The strongly reduced cell-free and cellular activities toward a PIF-pocket mutant of PKCζ suggested that the inhibitors most likely bound to the PIF-pocket on the kinase catalytic domain. Thus, using a rigidification strategy and by establishing and optimizing multiple mol. interactions with the binding site, the authors were able to significantly improve the potency of the previously reported PKCζ inhibitors.
- 332Atobe, M.; Serizawa, T.; Yamakawa, N.; Takaba, K.; Nagano, Y.; Yamaura, T.; Tanaka, E.; Tazumi, A.; Bito, S.; Ishiguro, M.; Kawanishi, M. Discovery of 4,6- and 5,7-disubstituted isoquinoline derivatives as a novel class of protein kinase C ζ inhibitors with fragment-merging strategy. J. Med. Chem. 2020, 63, 7143– 7162, DOI: 10.1021/acs.jmedchem.0c00449[ACS Full Text], [CAS], Google Scholar332https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtF2mtL7F&md5=d4c2517567518641c8581643e464b003Discovery of 4,6- and 5,7-Disubstituted Isoquinoline Derivatives as a Novel Class of Protein Kinase C ζ Inhibitors with Fragment-Merging StrategyAtobe, Masakazu; Serizawa, Takayuki; Yamakawa, Natsumi; Takaba, Kenichiro; Nagano, Yukiko; Yamaura, Toshiaki; Tanaka, Eiichi; Tazumi, Atsutoshi; Bito, Shino; Ishiguro, Masashi; Kawanishi, MasashiJournal of Medicinal Chemistry (2020), 63 (13), 7143-7162CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Two chem. series of novel protein kinase C ζ (PKCζ) inhibitors, 4,6-disubstituted and 5,7-disubstituted isoquinolines, were rapidly identified using our fragment merging strategy. This methodol. involves biochem. screening of a high concn. of a monosubstituted isoquinoline fragment library, then merging hit isoquinoline fragments into a single compd. Our strategy can be applied to the discovery of other challenging kinase inhibitors without protein-ligand structural information. Furthermore, our optimization effort identified the highly potent and orally available 5,7-isoquinoline 37(I) from the second chem. series. Compd. 37 showed good efficacy in a mouse collagen-induced arthritis model. The in vivo studies suggest that PKCζ inhibition is a novel target for rheumatoid arthritis (RA) and that 5,7-disubstituted isoquinoline 37 has the potential to elucidate the biol. consequences of PKCζ inhibition, specifically in terms of therapeutic intervention for RA.
- 333Slack-Davis, J. K.; Martin, K. H.; Tilghman, R. W.; Iwanicki, M.; Ung, E. J.; Autry, C.; Luzzio, M. J.; Cooper, B.; Kath, J. C.; Roberts, W. G.; Parsons, J. T. Cellular characterization of a novel focal adhesion kinase inhibitor. J. Biol. Chem. 2007, 282, 14845– 14852, DOI: 10.1074/jbc.M606695200[Crossref], [PubMed], [CAS], Google Scholar333https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXltFemtbY%253D&md5=38e97c67d37fbcbde006e6937ae4e360Cellular Characterization of a Novel Focal Adhesion Kinase InhibitorSlack-Davis, Jill K.; Martin, Karen H.; Tilghman, Robert W.; Iwanicki, Marcin; Ung, Ethan J.; Autry, Christopher; Luzzio, Michael J.; Cooper, Beth; Kath, John C.; Roberts, W. Gregory; Parsons, J. ThomasJournal of Biological Chemistry (2007), 282 (20), 14845-14852CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Focal adhesion kinase (FAK) is a member of a family of non-receptor protein-tyrosine kinases that regulates integrin and growth factor signaling pathways involved in cell migration, proliferation, and survival. FAK expression is increased in many cancers, including breast and prostate cancer. Here we describe perturbation of adhesion-mediated signaling with a FAK inhibitor, PF-573,228. In vitro, this compd. inhibited purified recombinant catalytic fragment of FAK with an IC50 of 4 nM. In cultured cells, PF-573,228 inhibited FAK phosphorylation on Tyr397 with an IC50 of 30-100 nM. Treatment of cells with concns. of PF-573,228 that significantly decreased FAK Tyr397 phosphorylation failed to inhibit cell growth or induce apoptosis. In contrast, treatment with PF-573,228 inhibited both chemotactic and haptotactic migration concomitant with the inhibition of focal adhesion turnover. These studies show that PF-573,228 serves as a useful tool to dissect the functions of FAK in integrin-dependent signaling pathways in normal and cancer cells and forms the basis for the generation of compds. amenable for preclin. and patient trials.
- 334Tso, S. C.; Lou, M.; Wu, C. Y.; Gui, W. J.; Chuang, J. L.; Morlock, L. K.; Williams, N. S.; Wynn, R. M.; Qi, X.; Chuang, D. T. Development of dihydroxyphenyl sulfonylisoindoline derivatives as liver-targeting pyruvate dehydrogenase kinase inhibitors. J. Med. Chem. 2017, 60, 1142– 1150, DOI: 10.1021/acs.jmedchem.6b01540[ACS Full Text], [CAS], Google Scholar334https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVKisrs%253D&md5=70c22064b3920f8ff871e0265818a201Development of Dihydroxyphenyl Sulfonylisoindoline Derivatives as Liver-Targeting Pyruvate Dehydrogenase Kinase InhibitorsTso, Shih-Chia; Lou, Mingliang; Wu, Cheng-Yang; Gui, Wen-Jun; Chuang, Jacinta L.; Morlock, Lorraine K.; Williams, Noelle S.; Wynn, R. Max; Qi, Xiangbing; Chuang, David T.Journal of Medicinal Chemistry (2017), 60 (3), 1142-1150CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Pyruvate dehydrogenase kinases 1-4 (PDK1-4) neg. control activity of the pyruvate dehydrogenase complex (PDC) and are up-regulated in obesity, diabetes, heart failure and cancer. The authors reported earlier two novel pan-PDK inhibitors PS8 [4-((5-hydroxyisoindolin-2-yl)sulfonyl)benzene-1,3-diol] and PS10 [2-((2,4-dihydroxyphenyl)sulfonyl)isoindoline-4,6-diol] that targeted the ATP-binding pocket in PDKs. Here, the authors developed a new generation of PDK inhibitors by extending the dihydroxyphenyl sulfonylisoindoline scaffold in PS8 and PS10 to the entrance region of the ATP-binding pocket in PDK2. The lead inhibitor PS46 [(S)-3-amino-4-(4-((2-((2,4-dihydroxyphenyl)sulfonyl)isoindolin-5-yl)amino)piperidin-1-yl)-4-oxobutanamide] (17) shows a ∼8-fold lower IC50 (58 nM) than 2 (456 nM). In the crystal structure, the asparagine moiety in 17 provides addnl. interactions with Glu 262 from PDK2. Treatment of diet-induced obese mice with 17 resulted in significant liver-specific augmentation of PDC activity, accompanied by improved glucose tolerance and drastically reduced hepatic steatosis. These findings support 17 as a potential glucose-lowering therapeutic targeting liver for obesity and type 2 diabetes.
- 335Lee, D.; Pagire, H. S.; Pagire, S. H.; Bae, E. J.; Dighe, M.; Kim, M.; Lee, K. M.; Jang, Y. K.; Jaladi, A. K.; Jung, K. Y.; Yoo, E. K.; Gim, H. E.; Lee, S.; Choi, W. I.; Chi, Y. I.; Song, J. S.; Bae, M. A.; Jeon, Y. H.; Lee, G. H.; Liu, K. H.; Lee, T.; Park, S.; Jeon, J. H.; Lee, I. K.; Ahn, J. H. Discovery of novel Pyruvate dehydrogenase kinase 4 inhibitors for potential oral treatment of metabolic diseases. J. Med. Chem. 2019, 62, 575– 588, DOI: 10.1021/acs.jmedchem.8b01168[ACS Full Text], [CAS], Google Scholar335https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXkvFakuw%253D%253D&md5=31b365c1d241ac0d121d6a4a7bc13a54Discovery of Novel Pyruvate Dehydrogenase Kinase 4 Inhibitors for Potential Oral Treatment of Metabolic DiseasesLee, Dahye; Pagire, Haushabhau S.; Pagire, Suvarna H.; Bae, Eun Jung; Dighe, Mahesh; Kim, Minhee; Lee, Kyu Myung; Jang, Yoon Kyung; Jaladi, Ashok Kumar; Jung, Kwan-Young; Yoo, Eun Kyung; Gim, Hee Eon; Lee, Seungmi; Choi, Won-Il; Chi, Young-In; Song, Jin Sook; Bae, Myung Ae; Jeon, Yong Hyun; Lee, Ga-Hyun; Liu, Kwang-Hyeon; Lee, Taeho; Park, Sungmi; Jeon, Jae-Han; Lee, In-Kyu; Ahn, Jin HeeJournal of Medicinal Chemistry (2019), 62 (2), 575-588CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Pyruvate dehydrogenase kinase 4 (PDK4) activation is assocd. with metabolic diseases including hyperglycemia, insulin resistance, allergies, and cancer. Structural modifications of hit anthraquinone led to the identification of a new series of allosteric PDK4 inhibitors. Among this series, compd. 8c showed promising in vitro activity with an IC50 value of 84 nM. Good metabolic stability, pharmacokinetic profiles, and possible metabolites were suggested. Compd. 8c improved glucose tolerance in diet-induced obese mice and ameliorated allergic reactions in a passive cutaneous anaphylaxis mouse model. Addnl., compd. 8c exhibited anticancer activity by controlling cell proliferation, transformation, and apoptosis. From the mol. docking studies, compd. 8c displayed optimal fitting in the lipoamide binding site (allosteric) with a full fitness, providing a new scaffold for drug development toward PDK4 inhibitors.
- 336Osgerby, L.; Lai, Y. C.; Thornton, P. J.; Amalfitano, J.; Le Duff, C. S.; Jabeen, I.; Kadri, H.; Miccoli, A.; Tucker, J. H. R.; Muqit, M. M. K.; Mehellou, Y. Kinetin riboside and its protides activate the parkinson’s disease associated PTEN-induced putative kinase 1 (PINK1) independent of mitochondrial depolarization. J. Med. Chem. 2017, 60, 3518– 3524, DOI: 10.1021/acs.jmedchem.6b01897[ACS Full Text], [CAS], Google Scholar336https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXkslKlt7s%253D&md5=bc90c5fa151f4c8e63d4a96a1297bc3aKinetin Riboside and Its ProTides Activate the Parkinson's Disease Associated PTEN-Induced Putative Kinase 1 (PINK1) Independent of Mitochondrial DepolarizationOsgerby, Laura; Lai, Yu-Chiang; Thornton, Peter J.; Amalfitano, Joseph; Le Duff, Cecile S.; Jabeen, Iqra; Kadri, Hachemi; Miccoli, Ageo; Tucker, James H. R.; Muqit, Miratul M. K.; Mehellou, YoucefJournal of Medicinal Chemistry (2017), 60 (8), 3518-3524CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Since loss of function mutations of PINK1 lead to early onset Parkinson's disease, there has been growing interest in the discovery of small mols. that amplify the kinase activity of PINK1. We herein report the design, synthesis, serum stability, and hydrolysis of four kinetin riboside ProTides. These ProTides, along with kinetin riboside, activated PINK1 in cells independent of mitochondrial depolarization. This highlights the potential of modified nucleosides and their phosphate prodrugs as treatments for neurodegenerative diseases.
- 337Meredith, E. L.; Ardayfio, O.; Beattie, K.; Dobler, M. R.; Enyedy, I.; Gaul, C.; Hosagrahara, V.; Jewell, C.; Koch, K.; Lee, W.; Lehmann, H.; McKinsey, T. A.; Miranda, K.; Pagratis, N.; Pancost, M.; Patnaik, A.; Phan, D.; Plato, C.; Qian, M.; Rajaraman, V.; Rao, C.; Rozhitskaya, O.; Ruppen, T.; Shi, J.; Siska, S. J.; Springer, C.; van Eis, M.; Vega, R. B.; von Matt, A.; Yang, L.; Yoon, T.; Zhang, J. H.; Zhu, N.; Monovich, L. G. Identification of orally available naphthyridine protein kinase D inhibitors. J. Med. Chem. 2010, 53, 5400– 5421, DOI: 10.1021/jm100075z[ACS Full Text], [CAS], Google Scholar337https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXovVCitbk%253D&md5=252f56b32d89af3cdda5f970f2f98e74Identification of Orally Available Naphthyridine Protein Kinase D InhibitorsMeredith, Erik L.; Ardayfio, Ophelia; Beattie, Kimberly; Dobler, Markus R.; Enyedy, Istvan; Gaul, Christoph; Hosagrahara, Vinayak; Jewell, Charles; Koch, Keith; Lee, Wendy; Lehmann, Hans Joerg; McKinsey, Timothy A.; Miranda, Karl; Pagratis, Nikos; Pancost, Margaret; Patnaik, Anup; Phan, Dillon; Plato, Craig; Qian, Ming; Rajaraman, Vasumathy; Rao, Chang; Rozhitskaya, Olga; Ruppen, Thomas; Shi, Jie; Siska, Sarah J.; Springer, Clayton; van Eis, Maurice; Vega, Richard B.; von Matt, Anette; Yang, Lihua; Yoon, Taeyoung; Zhang, Ji-Hu; Zhu, Na; Monovich, Lauren G.Journal of Medicinal Chemistry (2010), 53 (15), 5400-5421CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A novel 2,6-naphthyridine was identified by high throughput screen (HTS) as a dual protein kinase C/D (PKC/PKD) inhibitor. PKD inhibition in the heart was proposed as a potential antihypertrophic mechanism with application as a heart failure therapy. As PKC was previously identified as the immediate upstream activator of PKD, PKD vs PKC selectivity was essential to understand the effect of PKD inhibition in models of cardiac hypertrophy and heart failure. The present study describes the modification of the HTS hit to a series of prototype pan-PKD inhibitors with routine 1000-fold PKD vs PKC selectivity. Example compds. inhibited PKD activity in vitro, in cells, and in vivo following oral administration. Their effects on heart morphol. and function are discussed herein.
- 338Vincetti, P.; Caporuscio, F.; Kaptein, S.; Gioiello, A.; Mancino, V.; Suzuki, Y.; Yamamoto, N.; Crespan, E.; Lossani, A.; Maga, G.; Rastelli, G.; Castagnolo, D.; Neyts, J.; Leyssen, P.; Costantino, G.; Radi, M. Discovery of multitarget antivirals acting on both the dengue virus NS5-NS3 interaction and the host src/fyn kinases. J. Med. Chem. 2015, 58, 4964– 4975, DOI: 10.1021/acs.jmedchem.5b00108[ACS Full Text], [CAS], Google Scholar338https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXpsFaksro%253D&md5=43671e087a9f7c8b0735e7dd260eeadbDiscovery of Multitarget Antivirals Acting on Both the Dengue Virus NS5-NS3 Interaction and the Host Src/Fyn KinasesVincetti, Paolo; Caporuscio, Fabiana; Kaptein, Suzanne; Gioiello, Antimo; Mancino, Valentina; Suzuki, Youichi; Yamamoto, Naoki; Crespan, Emmanuele; Lossani, Andrea; Maga, Giovanni; Rastelli, Giulio; Castagnolo, Daniele; Neyts, Johan; Leyssen, Pieter; Costantino, Gabriele; Radi, MarcoJournal of Medicinal Chemistry (2015), 58 (12), 4964-4975CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)This study describes the discovery of novel dengue virus inhibitors targeting both a crucial viral protein-protein interaction and an essential host cell factor as a strategy to reduce the emergence of drug resistance. Starting from known c-Src inhibitors, a virtual screening was performed to identify mols. able to interact with a recently discovered allosteric pocket on the dengue virus NS5 polymerase. The selection of cheap-to-produce scaffolds and the exploration of the biol. relevant chem. space around them suggested promising candidates for chem. synthesis. A series of purines emerged as the most interesting candidates able to inhibit virus replication at low micromolar concns. with no significant toxicity to the host cell. Among the identified antivirals, compd. I proved to be 10 times more potent than ribavirin, showed a better selectivity index and represents the first-in-class DENV-NS5 allosteric inhibitor able to target both the virus NS5-NS3 interaction and the host kinases c-Src/Fyn.
- 339Imamura, K.; Izumi, Y.; Watanabe, A.; Tsukita, K.; Woltjen, K.; Yamamoto, T.; Hotta, A.; Kondo, T.; Kitaoka, S.; Ohta, A.; Tanaka, A.; Watanabe, D.; Morita, M.; Takuma, H.; Tamaoka, A.; Kunath, T.; Wray, S.; Furuya, H.; Era, T.; Makioka, K.; Okamoto, K.; Fujisawa, T.; Nishitoh, H.; Homma, K.; Ichijo, H.; Julien, J. P.; Obata, N.; Hosokawa, M.; Akiyama, H.; Kaneko, S.; Ayaki, T.; Ito, H.; Kaji, R.; Takahashi, R.; Yamanaka, S.; Inoue, H. The Src/c-Abl pathway is a potential therapeutic target in amyotrophic lateral sclerosis. Sci. Transl. Med. 2017, 9, eaaf3962 DOI: 10.1126/scitranslmed.aaf3962
- 340Prado, V.; Lence, E.; Maneiro, M.; Vazquez-Ucha, J. C.; Beceiro, A.; Thompson, P.; Hawkins, A. R.; Gonzalez-Bello, C. Targeting the motion of shikimate kinase: development of competitive inhibitors that stabilize an inactive open conformation of the enzyme. J. Med. Chem. 2016, 59, 5471– 5487, DOI: 10.1021/acs.jmedchem.6b00483[ACS Full Text], [CAS], Google Scholar340https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XnslWiurY%253D&md5=9022076b2c4efd51c65322374dfb7ed7Targeting the Motion of Shikimate Kinase: Development of Competitive Inhibitors that Stabilize an Inactive Open Conformation of the EnzymePrado, Veronica; Lence, Emilio; Maneiro, Maria; Vazquez-Ucha, Juan C.; Beceiro, Alejandro; Thompson, Paul; Hawkins, Alastair R.; Gonzalez-Bello, ConcepcionJournal of Medicinal Chemistry (2016), 59 (11), 5471-5487CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The large conformational changes obsd. by Mol. Dynamics simulation studies on the product release in the LID and shikimic acid binding (SB) domains of the shikimate kinase (SK) enzyme have been exploited in the development of reversible competitive inhibitors against SK from Mycobacterium tuberculosis and Helicobacter pylori. This enzyme is a recognized target for antibiotic drug discovery. The reported C5-substituted shikimic acid analogs interact with the dynamic apolar pocket that surrounds the C4 and C5 hydroxyl groups of the natural substrate, cause the opening of the LID and SB domains, and capture the essential arginine far from the ATP binding site as required for catalysis. The 3-nitrobenzyl 3e and 5-benzothiophenyl derivs. 3i proved to be the most potent inhibitors. An ester prodrug of 3i was the most efficient deriv. in achieving good in vitro activity against H. pylori, having a MIC value of 4 μg/mL.
- 341Mathews, T. P.; Kennedy, A. J.; Kharel, Y.; Kennedy, P. C.; Nicoara, O.; Sunkara, M.; Morris, A. J.; Wamhoff, B. R.; Lynch, K. R.; Macdonald, T. L. Discovery, biological evaluation, and structure-activity relationship of amidine based sphingosine kinase inhibitors. J. Med. Chem. 2010, 53, 2766– 2778, DOI: 10.1021/jm901860h[ACS Full Text], [CAS], Google Scholar341https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXivVajsbw%253D&md5=65dd6f8fe9a0d718b7491a8b919647ebDiscovery, Biological Evaluation, and Structure-Activity Relationship of Amidine Based Sphingosine Kinase InhibitorsMathews, Thomas P.; Kennedy, Andrew J.; Kharel, Yugesh; Kennedy, Perry C.; Nicoara, Oana; Sunkara, Manjula; Morris, Andrew J.; Wamhoff, Brian R.; Lynch, Kevin R.; MacDonald, Timothy L.Journal of Medicinal Chemistry (2010), 53 (7), 2766-2778CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Sphingosine 1-phosphate (S1P), a potent phospholipid growth and trophic factor, is synthesized in vivo by two sphingosine kinases. Thus these kinases have been proposed as important drug targets for treatment of hyperproliferative diseases and inflammation. We report here a new class of amidine-based sphingosine analogs that are competitive inhibitors of sphingosine kinases exhibiting varying degrees of enzyme selectivity. These inhibitors display KI values in the submicromolar range for both sphingosine kinases and, in cultured vascular smooth muscle cells, decrease S1P levels and initiate growth arrest.
- 342Boibessot, T.; Zschiedrich, C. P.; Lebeau, A.; Benimelis, D.; Dunyach-Remy, C.; Lavigne, J. P.; Szurmant, H.; Benfodda, Z.; Meffre, P. The rational design, synthesis, and antimicrobial properties of thiophene derivatives that inhibit bacterial histidine kinases. J. Med. Chem. 2016, 59, 8830– 8847, DOI: 10.1021/acs.jmedchem.6b00580[ACS Full Text], [CAS], Google Scholar342https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVChtrrO&md5=d19c39753e7fab31413fa38a8ebc2be9The Rational Design, Synthesis, and Antimicrobial Properties of Thiophene Derivatives That Inhibit Bacterial Histidine KinasesBoibessot, Thibaut; Zschiedrich, Christopher P.; Lebeau, Alexandre; Benimelis, David; Dunyach-Remy, Catherine; Lavigne, Jean-Philippe; Szurmant, Hendrik; Benfodda, Zohra; Meffre, PatrickJournal of Medicinal Chemistry (2016), 59 (19), 8830-8847CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The emergence of multi-drug-resistant bacteria emphasizes the urgent need for novel antibacterial compds. targeting unique cellular processes. Two-component signal transduction systems (TCSs) are commonly used by bacteria to couple environmental stimuli to adaptive responses, are absent in mammals, and are embedded in various pathogenic pathways. To attenuate these signaling pathways, we aimed to target the TCS signal transducer histidine kinase (HK) by focusing on their highly conserved ATP-binding domain. We used a structure-based drug design strategy that begins from an inhibitor-bound crystal structure and includes a significant no. of structurally simplifying "intuitive" modifications to arrive at the simple achiral, biaryl target structures. Thus, ligands were designed, leading to a series of thiophene derivs. These compds. were synthesized and evaluated in vitro against bacterial HKs. We identified eight compds. with significant inhibitory activities against these proteins, two of which exhibited broad-spectrum antimicrobial activity. The compds. were also evaluated as adjuvants for the treatment of resistant bacteria. One compd. was found to restore the sensitivity of these bacteria to the resp. antibiotics.
- 343Goswami, M.; Wilke, K. E.; Carlson, E. E. Rational design of selective adenine-based scaffolds for inactivation of Bacterial histidine kinases. J. Med. Chem. 2017, 60, 8170– 8182, DOI: 10.1021/acs.jmedchem.7b01066[ACS Full Text], [CAS], Google Scholar343https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFeiurrO&md5=ba1ffc268f101ee0fa08c3f8c3dcd54bRational Design of Selective Adenine-Based Scaffolds for Inactivation of Bacterial Histidine KinasesGoswami, Manibarsha; Wilke, Kaelyn E.; Carlson, Erin E.Journal of Medicinal Chemistry (2017), 60 (19), 8170-8182CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Bacterial histidine kinases (HKs) are quintessential regulatory enzymes found ubiquitously in bacteria. Apart from regulatory roles, they are also involved in the prodn. of virulence factors and conferring resistance to various antibiotics in pathogenic microbes. We have previously reported compds. that inhibit multiple HKs by targeting the conserved catalytic and ATP-binding (CA) domain. Herein, we conduct a detailed structure-activity relationship assessment of adenine-based inhibitors using biochem. and docking methods. These studies have lead to several observations. First, interaction of an inhibitor's amine group with the conserved, active-site Asp is essential for activity and likely dictates its orientation in the binding pocket. Second, a N-NH-N triad in the inhibitor scaffold is highly preferred for binding to conserved Gly:Asp:Asn residues. Lastly, hydrophobic, electron-withdrawing groups at several positions on the adenine core enhance potency. The selectivity of these inhibitors was tested against Heat Shock Protein 90 (HSP90), which possesses a similar ATP-binding fold. We found that groups that target the ATP-lid portion of the catalytic domain, such as a six-membered ring, confer selectivity for HKs.
- 344Martinez-Botella, G.; Breen, J. N.; Duffy, J. E.; Dumas, J.; Geng, B.; Gowers, I. K.; Green, O. M.; Guler, S.; Hentemann, M. F.; Hernandez-Juan, F. A.; Joseph-McCarthy, D.; Kawatkar, S.; Larsen, N. A.; Lazari, O.; Loch, J. T.; Macritchie, J. A.; McKenzie, A. R.; Newman, J. V.; Olivier, N. B.; Otterson, L. G.; Owens, A. P.; Read, J.; Sheppard, D. W.; Keating, T. A. Discovery of selective and potent inhibitors of gram-positive bacterial thymidylate kinase (TMK). J. Med. Chem. 2012, 55, 10010– 10021, DOI: 10.1021/jm3011806[ACS Full Text], [CAS], Google Scholar344https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVOhsL7P&md5=47d16055c461422d98fb0d8afb44dde2Discovery of Selective and Potent Inhibitors of Gram-Positive Bacterial Thymidylate Kinase (TMK)Martinez-Botella, Gabriel; Breen, John N.; Duffy, James E. S.; Dumas, Jacques; Geng, Bolin; Gowers, Ian K.; Green, Oluyinka M.; Guler, Satenig; Hentemann, Martin F.; Hernandez-Juan, Felix A.; Joseph-McCarthy, Diane; Kawatkar, Sameer; Larsen, Nicholas A.; Lazari, Ovadia; Loch, James T.; Macritchie, Jacqueline A.; McKenzie, Andrew R.; Newman, Joseph V.; Olivier, Nelson B.; Otterson, Linda G.; Owens, Andrew P.; Read, Jon; Sheppard, David W.; Keating, Thomas A.Journal of Medicinal Chemistry (2012), 55 (22), 10010-10021CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Thymidylate kinase (TMK) is an essential enzyme in bacterial DNA synthesis. The deoxythymidine monophosphate (dTMP) substrate binding pocket was targeted in a rational-design, structure-supported effort, yielding a unique series of antibacterial agents showing a novel, induced-fit binding mode. Lead optimization, aided by X-ray crystallog., led to picomolar inhibitors of both Streptococcus pneumoniae and Staphylococcus aureus TMK. MICs < 1 μg/mL were achieved against methicillin-resistant S. aureus (MRSA), S. pneumoniae, and vancomycin-resistant Enterococcus (VRE). Log D adjustments yielded single diastereomers 14 (TK-666) and 46, showing a broad antibacterial spectrum against Gram-pos. bacteria and excellent selectivity against the human thymidylate kinase ortholog.
- 345Naik, M.; Raichurkar, A.; Bandodkar, B. S.; Varun, B. V.; Bhat, S.; Kalkhambkar, R.; Murugan, K.; Menon, R.; Bhat, J.; Paul, B.; Iyer, H.; Hussein, S.; Tucker, J. A.; Vogtherr, M.; Embrey, K. J.; McMiken, H.; Prasad, S.; Gill, A.; Ugarkar, B. G.; Venkatraman, J.; Read, J.; Panda, M. Structure guided lead generation for M. tuberculosis thymidylate kinase (Mtb TMK): discovery of 3-cyanopyridone and 1,6-naphthyridin-2-one as potent inhibitors. J. Med. Chem. 2015, 58, 753– 766, DOI: 10.1021/jm5012947[ACS Full Text], [CAS], Google Scholar345https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVCku7jN&md5=3a9ec4e7eea4e656b12776f91091cebbStructure Guided Lead Generation for M. tuberculosis Thymidylate Kinase (Mtb TMK): Discovery of 3-Cyanopyridone and 1,6-Naphthyridin-2-one as Potent InhibitorsNaik, Maruti; Raichurkar, Anandkumar; Bandodkar, Balachandra S.; Varun, Begur V.; Bhat, Shantika; Kalkhambkar, Rajesh; Murugan, Kannan; Menon, Rani; Bhat, Jyothi; Paul, Beena; Iyer, Harini; Hussein, Syeed; Tucker, Julie A.; Vogtherr, Martin; Embrey, Kevin J.; McMiken, Helen; Prasad, Swati; Gill, Adrian; Ugarkar, Bheemarao G.; Venkatraman, Janani; Read, Jon; Panda, ManoranjanJournal of Medicinal Chemistry (2015), 58 (2), 753-766CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)M. tuberculosis thymidylate kinase (Mtb TMK) has been shown in vitro to be an essential enzyme in DNA synthesis. In order to identify novel leads for Mtb TMK, the authors performed a high throughput biochem. screen and an NMR based fragment screen through which the authors discovered two novel classes of inhibitors, 3-cyanopyridones and 1,6-naphthyridin-2-ones, resp. The authors describe three cyanopyridone subseries that arose during the hit to lead campaign, along with cocrystal structures of representatives with Mtb TMK. Structure aided optimization of the cyanopyridones led to single digit nanomolar inhibitors of Mtb TMK. Fragment based lead generation, augmented by crystal structures and the SAR from the cyanopyridones, enabled us to drive the potency of the 1,6-naphthyridin-2-one fragment hit from 500 μM to 200 nM while simultaneously improving the ligand efficiency. Cyanopyridone derivs. contg. sulfoxides and sulfones, e.g. I, showed cellular activity against M. tuberculosis. To the best of the knowledge, these compds. are the first reports of nonthymidine-like inhibitors of Mtb TMK.
- 346Philp, J.; Lawhorn, B. G.; Graves, A. P.; Shewchuk, L.; Rivera, K. L.; Jolivette, L. J.; Holt, D. A.; Gatto, G. J., Jr; Kallander, L. S. 4,6-Diaminopyrimidines as highly preferred Troponin I-interacting kinase (TNNI3K) inhibitors. J. Med. Chem. 2018, 61, 3076– 3088, DOI: 10.1021/acs.jmedchem.8b00125[ACS Full Text], [CAS], Google Scholar346https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXltFCjsro%253D&md5=b3c93adce5f2f02e6b4a805e579d2e744,6-Diaminopyrimidines as Highly Preferred Troponin I-Interacting Kinase (TNNI3K) InhibitorsPhilp, Joanne; Lawhorn, Brian G.; Graves, Alan P.; Shewchuk, Lisa; Rivera, Katrina L.; Jolivette, Larry J.; Holt, Dennis A.; Gatto, Gregory J.; Kallander, Lara S.Journal of Medicinal Chemistry (2018), 61 (7), 3076-3088CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Structure-guided progression of a purine-derived series of TNNI3K inhibitors directed design efforts that produced a novel series of 4,6-diaminopyrimidine inhibitors, an emerging kinase binding motif. Herein, the authors report a detailed understanding of the intrinsic conformational preferences of the scaffold, which impart high specificity for TNNI3K. Further manipulation of the template based on the conformational anal. and addnl. structure-activity relationship studies provided enhancements in kinase selectivity and pharmacokinetics that furnished an advanced series of potent inhibitors. The optimized compds. (e.g., GSK854) are suitable leads for identifying new cardiac medicines and have been employed as in vivo tools in investigational studies aimed at defining the role of TNNI3K within heart failure.
- 347Lawhorn, B. G.; Philp, J.; Zhao, Y.; Louer, C.; Hammond, M.; Cheung, M.; Fries, H.; Graves, A. P.; Shewchuk, L.; Wang, L.; Cottom, J. E.; Qi, H.; Zhao, H.; Totoritis, R.; Zhang, G.; Schwartz, B.; Li, H.; Sweitzer, S.; Holt, D. A.; Gatto, G. J., Jr; Kallander, L. S. Identification of purines and 7-deazapurines as potent and selective type I inhibitors of Troponin I-interacting kinase (TNNI3K). J. Med. Chem. 2015, 58, 7431– 7448, DOI: 10.1021/acs.jmedchem.5b00931[ACS Full Text], [CAS], Google Scholar347https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVygs7rN&md5=d4a66f1ee1b5d62a5443225aca9bcb12Identification of Purines and 7-Deazapurines as Potent and Selective Type I Inhibitors of Troponin I-Interacting Kinase (TNNI3K)Lawhorn, Brian G.; Philp, Joanne; Zhao, Yongdong; Louer, Christopher; Hammond, Marlys; Cheung, Mui; Fries, Harvey; Graves, Alan P.; Shewchuk, Lisa; Wang, Liping; Cottom, Joshua E.; Qi, Hongwei; Zhao, Huizhen; Totoritis, Rachel; Zhang, Guofeng; Schwartz, Benjamin; Li, Hu; Sweitzer, Sharon; Holt, Dennis A.; Gatto, Gregory J., Jr.; Kallander, Lara S.Journal of Medicinal Chemistry (2015), 58 (18), 7431-7448CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of cardiac troponin I-interacting kinase (TNNI3K) inhibitors arising from 3-((9H-purin-6-yl)amino)-N-methyl-benzenesulfonamide (1) is disclosed along with fundamental structure-function relationships that delineate the role of each element of 1 for TNNI3K recognition. An X-ray structure of 1 bound to TNNI3K confirmed its Type I binding mode and is used to rationalize the structure-activity relationship and employed to design potent, selective, and orally bioavailable TNNI3K inhibitors. Identification of the 7-deazapurine heterocycle as a superior template (vs purine) and its elaboration by introduction of C4-benzenesulfonamide and C7- and C8-7-deazapurine substituents produced compds. with substantial improvements in potency (>1000-fold), general kinase selectivity (10-fold improvement), and pharmacokinetic properties (>10-fold increase in poDNAUC). Optimal members of the series have properties suitable for use in in vitro and in vivo expts. aimed at elucidating the role of TNNI3K in cardiac biol. and serve as leads for developing novel heart failure medicines.
- 348Tear, W. F.; Bag, S.; Diaz-Gonzalez, R.; Ceballos-Perez, G.; Rojas-Barros, D. I.; Cordon-Obras, C.; Perez-Moreno, G.; Garcia-Hernandez, R.; Martinez-Martinez, M. S.; Ruiz-Perez, L. M.; Gamarro, F.; Gonzalez Pacanowska, D.; Caffrey, C. R.; Ferrins, L.; Manzano, P.; Navarro, M.; Pollastri, M. P. Selectivity and physicochemical optimization of repurposed pyrazolo[1,5-b]pyridazines for the treatment of human african trypanosomiasis. J. Med. Chem. 2020, 63, 756– 783, DOI: 10.1021/acs.jmedchem.9b01741[ACS Full Text], [CAS], Google Scholar348https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisVWqsLnJ&md5=a214fe962c7e0b38f45b27eedb37fe2aSelectivity and Physicochemical Optimization of Repurposed Pyrazolo[1,5-b]pyridazines for the Treatment of Human African TrypanosomiasisTear, Westley F.; Bag, Seema; Diaz-Gonzalez, Rosario; Ceballos-Perez, Gloria; Rojas-Barros, Domingo I.; Cordon-Obras, Carlos; Perez-Moreno, Guiomar; Garcia-Hernandez, Raquel; Martinez-Martinez, Maria Santos; Ruiz-Perez, Luis Miguel; Gamarro, Francisco; Gonzalez Pacanowska, Dolores; Caffrey, Conor R.; Ferrins, Lori; Manzano, Pilar; Navarro, Miguel; Pollastri, Michael P.Journal of Medicinal Chemistry (2020), 63 (2), 756-783CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)From a high-throughput screen of 42 444 known human kinases inhibitors, a pyrazolo[1,5-b]pyridazine scaffold was identified to begin optimization for the treatment of human African trypanosomiasis. Previously reported data for analogous compds. against human kinases GSK-3β, CDK-2, and CDK-4 were leveraged to try to improve the selectivity of the series, resulting in 23a which showed selectivity for T. b. brucei over these three human enzymes. In parallel, properties known to influence the absorption, distribution, metab., and excretion (ADME) profile of the series were optimized resulting in 20g being progressed into an efficacy study in mice. Though 20g showed toxicity in mice, it also demonstrated CNS penetration in a PK study and significant redn. of parasitemia in four out of the six mice.
- 349Dubreuil, P.; Letard, S.; Ciufolini, M.; Gros, L.; Humbert, M.; Casteran, N.; Borge, L.; Hajem, B.; Lermet, A.; Sippl, W.; Voisset, E.; Arock, M.; Auclair, C.; Leventhal, P. S.; Mansfield, C. D.; Moussy, A.; Hermine, O. Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. PLoS One 2009, 4, e7258 DOI: 10.1371/journal.pone.0007258
- 350Ouyang, L.; Zhang, L.; Zhang, S.; Yao, D.; Zhao, Y.; Wang, G.; Fu, L.; Lei, P.; Liu, B. Small-molecule activator of unc-51-like kinase 1 (ULK1) that induces cytoprotective autophagy for parkinson’s disease treatment. J. Med. Chem. 2018, 61, 2776– 2792, DOI: 10.1021/acs.jmedchem.7b01575[ACS Full Text], [CAS], Google Scholar350https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXlt1Kktr8%253D&md5=f9076a7c130d27308c61632311e6169fSmall-Molecule Activator of UNC-51-Like Kinase 1 (ULK1) That Induces Cytoprotective Autophagy for Parkinson's Disease TreatmentOuyang, Liang; Zhang, Lan; Zhang, Shouyue; Yao, Dahong; Zhao, Yuqian; Wang, Guan; Fu, Leilei; Lei, Peng; Liu, BoJournal of Medicinal Chemistry (2018), 61 (7), 2776-2792CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)UNC-51-like kinase 1 (ULK1), the yeast Atg1 ortholog, is the sole serine-threonine kinase and initiating enzyme in autophagy, which may be regarded as a target in Parkinson's disease (PD). Herein, the authors discovered a small mol. 33i (BL-918, ((R)-2-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-N-(2,4-difluorophenyl)-2-phenylacetamide)) as a potent activator of ULK1 by structure-based drug design. Subsequently, some key amino acid residues (Arg 18, Lys 50, Asn 86, and Tyr 89) were found to be crucial to the binding pocket between ULK1 and 33i by site-directed mutagenesis. Moreover, the authors found that 33i induced autophagy via the ULK complex in SH-SY5Y cells. Intriguingly, this activator displayed a cytoprotective effect on MPP+-treated SH-SY5Y cells, as well as protected against MPTP-induced motor dysfunction and loss of dopaminergic neurons by targeting ULK1-modulated autophagy in mouse models of PD. Together, these results demonstrate the therapeutic potential to target ULK1, and 33i, the novel activator of ULK1, may serve as a candidate drug for future PD treatment.
- 351Meredith, E. L.; Mainolfi, N.; Poor, S.; Qiu, Y.; Miranda, K.; Powers, J.; Liu, D.; Ma, F.; Solovay, C.; Rao, C.; Johnson, L.; Ji, N.; Artman, G.; Hardegger, L.; Hanks, S.; Shen, S.; Woolfenden, A.; Fassbender, E.; Sivak, J. M.; Zhang, Y.; Long, D.; Cepeda, R.; Liu, F.; Hosagrahara, V. P.; Lee, W.; Tarsa, P.; Anderson, K.; Elliott, J.; Jaffee, B. Discovery of oral VEGFR-2 inhibitors with prolonged ocular retention that are efficacious in models of wet age-related macular degeneration. J. Med. Chem. 2015, 58, 9273– 9286, DOI: 10.1021/acs.jmedchem.5b01227[ACS Full Text], [CAS], Google Scholar351https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVehs7fF&md5=11ee9095e9eb62c548dec995a9c369ddDiscovery of Oral VEGFR-2 Inhibitors with Prolonged Ocular Retention That Are Efficacious in Models of Wet Age-Related Macular DegenerationMeredith, Erik L.; Mainolfi, Nello; Poor, Stephen; Qiu, Yubin; Miranda, Karl; Powers, James; Liu, Donglei; Ma, Fupeng; Solovay, Catherine; Rao, Chang; Johnson, Leland; Ji, Nan; Artman, Gerald; Hardegger, Leo; Hanks, Shawn; Shen, Siyuan; Woolfenden, Amber; Fassbender, Elizabeth; Sivak, Jeremy M.; Zhang, Yiqin; Long, Debby; Cepeda, Rosemarie; Liu, Fang; Hosagrahara, Vinayak P.; Lee, Wendy; Tarsa, Peter; Anderson, Karen; Elliott, Jason; Jaffee, BruceJournal of Medicinal Chemistry (2015), 58 (23), 9273-9286CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The benefit of intravitreal anti-VEGF therapy in treating wet age-related macular degeneration (AMD) is well established. Identification of VEGFR-2 inhibitors with optimal ADME properties for an ocular indication provides opportunities for dosing routes beyond intravitreal injection. The authors employed a high-throughput in vivo screening strategy with rodent models of choroidal neovascularization and iterative compd. design to identify VEGFR-2 inhibitors with potential to benefit wet AMD patients. These compds., e.g. I, demonstrate preferential ocular tissue distribution and efficacy after oral administration while minimizing systemic exposure.
- 352Adams, C. M.; Anderson, K.; Artman, G., 3rd; Bizec, J. C.; Cepeda, R.; Elliott, J.; Fassbender, E.; Ghosh, M.; Hanks, S.; Hardegger, L. A.; Hosagrahara, V. P.; Jaffee, B.; Jendza, K.; Ji, N.; Johnson, L.; Lee, W.; Liu, D.; Liu, F.; Long, D.; Ma, F.; Mainolfi, N.; Meredith, E. L.; Miranda, K.; Peng, Y.; Poor, S.; Powers, J.; Qiu, Y.; Rao, C.; Shen, S.; Sivak, J. M.; Solovay, C.; Tarsa, P.; Woolfenden, A.; Zhang, C.; Zhang, Y. The discovery of N-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-((6- ((methylamino)methyl)pyrimidin-4-yl)oxy)-1H-indole-1-carboxamide (Acrizanib), a VEGFR-2 inhibitor specifically designed for topical ocular delivery, as a therapy for neovascular age-related macular degeneration. J. Med. Chem. 2018, 61, 1622– 1635, DOI: 10.1021/acs.jmedchem.7b01731[ACS Full Text], [CAS], Google Scholar352https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitFSjsLg%253D&md5=21b5661580dda231c590bc7505e7be0eThe Discovery of N-(1-Methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-((6- ((methylamino)methyl)pyrimidin-4-yl)oxy)-1H-indole-1-carboxamide (Acrizanib), a VEGFR-2 Inhibitor Specifically Designed for Topical Ocular Delivery, as a Therapy for Neovascular Age-Related Macular DegenerationAdams, Christopher M.; Anderson, Karen; Artman, Gerald; Bizec, Jean-Claude; Cepeda, Rosemarie; Elliott, Jason; Fassbender, Elizabeth; Ghosh, Malay; Hanks, Shawn; Hardegger, Leo A.; Hosagrahara, Vinayak P.; Jaffee, Bruce; Jendza, Keith; Ji, Nan; Johnson, Leland; Lee, Wendy; Liu, Donglei; Liu, Fang; Long, Debby; Ma, Fupeng; Mainolfi, Nello; Meredith, Erik L.; Miranda, Karl; Peng, Yao; Poor, Stephen; Powers, James; Qiu, Yubin; Rao, Chang; Shen, Siyuan; Sivak, Jeremy M.; Solovay, Catherine; Tarsa, Peter; Woolfenden, Amber; Zhang, Chun; Zhang, YiqinJournal of Medicinal Chemistry (2018), 61 (4), 1622-1635CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A noninvasive topical ocular therapy for the treatment of neovascular or "wet" age-related macular degeneration would provide a patient administered alternative to the current std. of care, which requires physician administered intravitreal injections. This manuscript describes a novel strategy for the use of in vivo models of choroidal neovascularization (CNV) as the primary means of developing SAR related to efficacy from topical administration. Ultimately, this effort led to the discovery of acrizanib (LHA510), a small-mol. VEGFR-2 inhibitor with potency and efficacy in rodent CNV models, limited systemic exposure after topical ocular administration, multiple formulation options, and an acceptable rabbit ocular PK profile.
- 353Yamada, K.; Levell, J.; Yoon, T.; Kohls, D.; Yowe, D.; Rigel, D. F.; Imase, H.; Yuan, J.; Yasoshima, K.; DiPetrillo, K.; Monovich, L.; Xu, L.; Zhu, M.; Kato, M.; Jain, M.; Idamakanti, N.; Taslimi, P.; Kawanami, T.; Argikar, U. A.; Kunjathoor, V.; Xie, X.; Yagi, Y. I.; Iwaki, Y.; Robinson, Z.; Park, H. M. Optimization of allosteric With-no-lysine (WNK) kinase inhibitors and efficacy in rodent hypertension models. J. Med. Chem. 2017, 60, 7099– 7107, DOI: 10.1021/acs.jmedchem.7b00708[ACS Full Text], [CAS], Google Scholar353https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1KgtLzF&md5=70c1888c78cf9df946ca48b1887982f9Optimization of Allosteric With-No-Lysine (WNK) Kinase Inhibitors and Efficacy in Rodent Hypertension ModelsYamada, Ken; Levell, Julian; Yoon, Taeyong; Kohls, Darcy; Yowe, David; Rigel, Dean F.; Imase, Hidetomo; Yuan, Jun; Yasoshima, Kayo; DiPetrillo, Keith; Monovich, Lauren; Xu, Lingfei; Zhu, Meicheng; Kato, Mitsunori; Jain, Monish; Idamakanti, Neeraja; Taslimi, Paul; Kawanami, Toshio; Argikar, Upendra A.; Kunjathoor, Vidya; Xie, Xiaoling; Yagi, Yukiko I.; Iwaki, Yuki; Robinson, Zachary; Park, Hyi-ManJournal of Medicinal Chemistry (2017), 60 (16), 7099-7107CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The obsd. structure-activity relationship (SAR) of three distinct ATP noncompetitive With-No-Lysine (WNK) kinase inhibitor series, together with a crystal structure of a previously disclosed allosteric inhibitor bound to WNK1, led to an overlay hypothesis defining core and side-chain relationships across the different series. This in turn enabled an efficient optimization through scaffold morphing, resulting in compds. with a good balance of selectivity, cellular potency and pharmacokinetic profile, which were suitable for in vivo proof-of-concept studies. When dosed orally, the optimized compd. reduced blood pressure in mice overexpressing human WNK1 and in spontaneously hypertensive rats (SHR), and induced diuresis, natriuresis, kaliuresis and blood pressure in SHR, confirming that this mechanism of inhibition of WNK kinase activity is effective at regulating cardiovascular homeostasis.
- 354Pietri, M.; Dakowski, C.; Hannaoui, S.; Alleaume-Butaux, A.; Hernandez-Rapp, J.; Ragagnin, A.; Mouillet-Richard, S.; Haik, S.; Bailly, Y.; Peyrin, J. M.; Launay, J. M.; Kellermann, O.; Schneider, B. PDK1 decreases TACE-mediated α-secretase activity and promotes disease progression in prion and Alzheimer’s diseases. Nat. Med. 2013, 19, 1124– 1131, DOI: 10.1038/nm.3302[Crossref], [PubMed], [CAS], Google Scholar354https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1yltrjP&md5=4292823b5977c5f0d241d95f55b1e87dPDK1 decreases TACE-mediated α-secretase activity and promotes disease progression in prion and Alzheimer's diseasesPietri, Mathea; Dakowski, Caroline; Hannaoui, Samia; Alleaume-Butaux, Aurelie; Hernandez-Rapp, Julia; Ragagnin, Audrey; Mouillet-Richard, Sophie; Haik, Stephane; Bailly, Yannick; Peyrin, Jean-Michel; Launay, Jean-Marie; Kellermann, Odile; Schneider, BenoitNature Medicine (New York, NY, United States) (2013), 19 (9), 1124-1131CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)α-Secretase-mediated cleavage of amyloid precursor protein (APP) precludes formation of neurotoxic amyloid-β (Aβ) peptides, and α-cleavage of cellular prion protein (PrPC) prevents its conversion into misfolded, pathogenic prions (PrPSc). The mechanisms leading to decreased α-secretase activity in Alzheimer's and prion disease remain unclear. Here, we find that tumor necrosis factor-α-converting enzyme (TACE)-mediated α-secretase activity is impaired at the surface of neurons infected with PrPSc or isolated from APP-transgenic mice with amyloid pathol. 3-phosphoinositide-dependent kinase-1 (PDK1) activity is increased in neurons infected with prions or affected by Aβ deposition and in the brains of individuals with Alzheimer's disease. PDK1 induces phosphorylation and caveolin-1-mediated internalization of TACE. This dysregulation of TACE increases PrPSc and Aβ accumulation and reduces shedding of TNF-α receptor type 1 (TNFR1). Inhibition of PDK1 promotes localization of TACE to the plasma membrane, restores TACE-dependent α-secretase activity and cleavage of APP, PrPC and TNFR1, and attenuates PrPSc- and Aβ-induced neurotoxicity. In mice, inhibition or siRNA-mediated silencing of PDK1 extends survival and reduces motor impairment following PrPSc infection and in APP-transgenic mice reduces Alzheimer's disease-like pathol. and memory impairment.
- 355Coffey, G.; Betz, A.; DeGuzman, F.; Pak, Y.; Inagaki, M.; Baker, D. C.; Hollenbach, S. J.; Pandey, A.; Sinha, U. The novel kinase inhibitor PRT062070 (Cerdulatinib) demonstrates efficacy in models of autoimmunity and B-cell cancer. J. Pharmacol. Exp. Ther. 2014, 351, 538– 548, DOI: 10.1124/jpet.114.218164[Crossref], [PubMed], [CAS], Google Scholar355https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvFyhsbbF&md5=caed39628d643e4087ba88f7eaa51326The novel kinase inhibitor PRT062070 (Cerdulatinib) demonstrates efficacy in models of autoimmunity and B-cell cancerCoffey, Greg; Betz, Andreas; DeGuzman, Francis; Pak, Yvonne; Inagaki, Mayuko; Baker, Dale C.; Hollenbach, Stanley J.; Pandey, Anjali; Sinha, UmaJournal of Pharmacology and Experimental Therapeutics (2014), 351 (3), 538-548, 11 pp.CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)The heterogeneity and severity of certain autoimmune diseases and B-cell malignancies warrant simultaneous targeting of multiple disease-relevant signaling pathways. Dual inhibition of spleen tyrosine kinase (SYK) and Janus kinase (JAK) represents such a strategy and may elicit several benefits relative to selective kinase inhibition, such as gaining control over a broader array of disease etiologies, reducing probability of selection for bypass disease mechanisms, and the potential that an overall lower level suppression of individual targets may be sufficient to modulate disease activity. To this end, we provide data on the discovery and preclin. development of PRT062070 [4-(cyclopropylamino)-2-({4-[4-(ethylsulfonyl)piperazin-1-yl]phenyl}amino)pyrimidine-5-carboxamide hydrochloride], an orally active kinase inhibitor that demonstrates activity against SYK and JAK. Cellular assays demonstrated specific inhibitory activity against signaling pathways that use SYK and JAK1/3. Limited inhibition of JAK2 was obsd., and PRT062070 did not inhibit phorbol 12-myristate 13-acetate-mediated signaling or activation in B and T cells nor T-cell antigen receptor-mediated signaling in T cells, providing evidence for selectivity of action. Potent antitumor activity was obsd. in a subset of B-cell lymphoma cell lines. After oral dosing, PRT062070 suppressed inflammation and autoantibody generation in a rat collagen-induced arthritis model and blocked B-cell activation and splenomegaly in a mouse model of chronic B-cell antigen receptor stimulation. PRT062070 is currently under evaluation in a phase I dose escalation study in patients with B-cell leukemia and lymphoma (NCT01994382), with proof-of-concept studies in humans planned to assess therapeutic potential in autoimmune and malignant diseases.
- 356Smyth, L. A.; Collins, I. Measuring and interpreting the selectivity of protein kinase inhibitors. J. Chem. Biol. 2009, 2, 131– 151, DOI: 10.1007/s12154-009-0023-9[Crossref], [PubMed], [CAS], Google Scholar356https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MrkslGqtA%253D%253D&md5=f78ff1202a949a71ffd65e804298c37fMeasuring and interpreting the selectivity of protein kinase inhibitorsSmyth Lynette A; Collins IanJournal of chemical biology (2009), 2 (3), 131-51 ISSN:1864-6158.Protein kinase inhibitors are a well-established class of clinically useful drugs, particularly for the treatment of cancer. Achieving inhibitor selectivity for particular protein kinases often remains a significant challenge in the development of new small molecules as drugs or as tools for chemical biology research. This review summarises the methodologies available for measuring kinase inhibitor selectivity, both in vitro and in cells. The interpretation of kinase inhibitor selectivity data is discussed, particularly with reference to the structural biology of the protein targets. Measurement and prediction of kinase inhibitor selectivity will be important for the development of new multi-targeted kinase inhibitors.
- 357Panicker, R. C.; Chattopadhaya, S.; Coyne, A. G.; Srinivasan, R. Allosteric small-molecule serine/threonine kinase inhibitors. Adv. Exp. Med. Biol. 2019, 1163, 253– 278, DOI: 10.1007/978-981-13-8719-7_11[Crossref], [PubMed], [CAS], Google Scholar357https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXosFeht7Y%253D&md5=aff162e9dee91f765c95fadb2ed7c487Allosteric Small-Molecule Serine/Threonine Kinase InhibitorsPanicker, Resmi C.; Chattopadhaya, Souvik; Coyne, Anthony G.; Srinivasan, RajavelAdvances in Experimental Medicine and Biology (2019), 1163 (Protein Allostery in Drug Discovery), 253-278CODEN: AEMBAP; ISSN:2214-8019. (Springer)A review. Deregulation of protein kinase activity has been linked to many diseases ranging from cancer to AIDS and neurodegenerative diseases. Not surprisingly, drugging the human kinome - the complete set of kinases encoded by the human genome - has been one of the major drug discovery pipelines. Majority of the approved clin. kinase inhibitors target the ATP binding site of kinases. However, the remarkable sequence and structural similarity of ATP binding pockets of kinases make selective inhibition of kinases a daunting task. To circumvent these issues, allosteric inhibitors that target sites other than the orthosteric ATP binding pocket have been developed. The structural diversity of the allosteric sites allows these inhibitors to have higher selectivity, lower toxicity and improved physiochem. properties and overcome drug resistance assocd. with the use of conventional kinase inhibitors. In this chapter, we will focus on the allosteric inhibitors of selected serine/threonine kinases, outline the benefits of using these inhibitors and discuss the challenges and future opportunities.
- 358Wu, P.; Clausen, M. H.; Nielsen, T. E. Allosteric small-molecule kinase inhibitors. Pharmacol. Ther. 2015, 156, 59– 68, DOI: 10.1016/j.pharmthera.2015.10.002[Crossref], [PubMed], [CAS], Google Scholar358https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs12qsb3N&md5=26e4658d325b8f016be29df27bf69ec2Allosteric small-molecule kinase inhibitorsWu, Peng; Clausen, Mads H.; Nielsen, Thomas E.Pharmacology & Therapeutics (2015), 156 (), 59-68CODEN: PHTHDT; ISSN:0163-7258. (Elsevier)Small-mol. kinase inhibitors are invaluable targeted therapeutics for the treatment of various human diseases, esp. cancers. While the majority of approved and developed preclin. small-mol. inhibitors are characterized as type I or type II inhibitors that target the ATP-binding pocket of kinases, the remarkable sequential and structural similarity among ATP pockets renders the selective inhibition of kinases a daunting challenge. Therefore, targeting allosteric pockets of kinases outside the highly conversed ATP pocket has been proposed as a promising alternative to overcome current barriers of kinase inhibitors, including poor selectivity and emergence of drug resistance. In spite of the small no. of identified allosteric inhibitors in comparison with that of inhibitors targeting the ATP pocket, encouraging results, such as the FDA-approval of the first small-mol. allosteric inhibitor trametinib in 2013, the progress of more than 10 other allosteric inhibitors in clin. trials, and the emergence of a pipeline of highly selective and potent preclin. mols., have been reported in the past decade. In this article, we present the current knowledge on allosteric inhibition in terms of conception, classification, potential advantages, and summarized debatable topics in the field. Recent progress and allosteric inhibitors that were identified in the past three years are highlighted in this paper.
- 359Groppe, J. C. Induced degradation of protein kinases by bifunctional small molecules: a next-generation strategy. Expert Opin. Drug Discovery 2019, 14, 1237– 1253, DOI: 10.1080/17460441.2019.1660641[Crossref], [PubMed], [CAS], Google Scholar359https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhslOltLzF&md5=1722b0f3b5d81952abeae40962a62ca6Induced degradation of protein kinases by bifunctional small molecules: a next-generation strategyGroppe, Jay C.Expert Opinion on Drug Discovery (2019), 14 (12), 1237-1253CODEN: EODDBX; ISSN:1746-0441. (Taylor & Francis Ltd.)A review. Protein kinases are a major target for small-mol. drug development. However, relatively few compds. are free of off-target toxicity and reach the clinic. Because the 500-plus kinases share conserved ATP-binding clefts, the site targeted by competitive inhibitors, generation of specific therapeutics remains a nearly intractable challenge. Inducing degrdn., instead of inhibition by occupancy-driven drugs, is an emerging strategy that offers the long-sought specificity, as well as mechanistic benefits. Currently approved inhibitors require steady-state binding and leave proteins intact for interactions in multi-protein complexes. After a general background about induced protein degrdn., perspectives on protein kinases are provided. Induced degrdn. by state-of-the-art compds. (proteolysis-targeting chimeras, PROTACs) has been shown for protein kinases, albeit in early pre-clin. stages. Further work is required to expand the no. of enzymes that could be exploited to direct proteins for degrdn. by ubiquitylation. In addn., despite the simple modularity of the chimeras, generation of hits will require empirical approaches due to the role of protein-protein interactions and distribution of tagging sites. However, given the advantages of degrdn., drug discovery efforts targeting protein kinases should increasingly shift toward generation and screening of inducers of degrdn. and away from occupancy-based inhibitors of old.